Antimitotic amides for the treatment of cancer and proliferative disorders

ABSTRACT

Novel, antimitotic heteroaryl amides and pharmaceutically acceptable salts of Formula I where Ar, R 5 , R 6 , R 8 , R 9 , R 11 , X 1 , and X 2  are as defined herein, as compounds for treatment and prevention of cancer and proliferative diseases and disorders.

REFERENCE TO EARLIER FILED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/011,589, filed Sep. 3, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/024,407, filed Jun. 29, 2019, which is acontinuation of U.S. patent application Ser. No. 15/120,470, filed Aug.19, 2016, which is a 371 national phase of International Application No.PCT/US2015/016928, filed Feb. 20, 2015, which claims the benefit under35 U.S.C. § 119(e) of U.S. Provisional Patent Application No.61/942,956, filed Feb. 21, 2014, the disclosures of which areincorporated, in their entirety, by this reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to biologically active chemical compounds,namely heteroaryl amides for treating proliferative disorders such ascancer.

BACKGROUND

Cancer is currently the second leading cause of death in the UnitedStates of America, the European Union and Japan and represents a growingworld-wide problem. According to the world health organization, annualglobal cancer deaths are projected to reach 15 million by 2020.

Existing cancer drugs seek to exploit intrinsic differences betweencancer cells and normal cells to selectively eradicate the malignantcell population whilst minimizing effects on normal cells that may leadto potentially harmful side-effects. Whereas normal cells are typicallyquiescent, uncontrolled cellular proliferation is a hallmark of cancercells and this distinguishing feature underlies the efficacy of mostclinically used chemotherapies.

Compounds that directly target cell division or mitosis are amongst themost successful and widely used anti-cancer drugs, either as part ofcombinatorial drug regimens or as first-line single agent therapies. Themost widely used anti-mitotic agents are the taxanes and the vincaalkaloids, plant derived natural products, which respectively stabilizeand destabilize microtubule networks. In addition to these compounds,other natural product derivatives have recently been approved for cancertreatment including the tubulin stabilizing epothilone, Ixabepilone andthe tubulin detastablizing halichondrin-B analog Eribulin. Colchicine,another natural product tubulin polymerization inhibitor is approved forindications other than cancer.

The natural product-based anti-mitotics face a number of intrinsiclimitations which severely restrict their clinical utility, includingtheir difficulty of synthesis and/or isolation from natural sources,poor solubility, low bioavailability, systemic toxicities that includeneurotoxicity and the development of drug resistance. All or some ofthese limitations may be overcome by developing synthetic small moleculecompounds that work through similar anti-mitotic mechanisms.

Consequently, there remains a great need to develop new, synthetic smallmolecule anti-mitotic agents that may overcome the limitations of theexisting approved natural products and extend the scope andeffectiveness of this class of therapeutics.

SUMMARY

Compounds, salts, prodrugs, and solvates of formula I are disclosed,

wherein the Ar, X¹, X², R⁵, R⁶, R⁸, R⁹, and R¹¹ have the meaningsdefined hereafter. The compounds may be used for treatment andprevention of cancer and proliferative diseases and disorders.

In some embodiments, Ar is an optionally substituted phenyl oroptionally substituted 5-membered heteroaryl ring, each having 0 to 5substituents selected from halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A),—OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; provided that when Ar is phenyl, at least oneortho-substitution is —H; X¹ is selected from N and CR⁷; X² is selectedfrom N and CR¹⁰; each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ is independentlyselected from —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B),—OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; each of R⁸ and R⁹ is independently selectedfrom H, halogen, —OR^(A), —NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B),—SH, and —SR^(A); each of R^(A), R^(B), and R^(C), when present, isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″,—NR′″C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; R′, R″, andR′″ are each independently —H, unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₆ cycloalkyl, or R′ and R″ together with the atomswhich they substitute form a substituted or unsubstituted 5-, 6-, or7-membered ring; provided that when X¹ is N, X² is CH, and Ar isunsubstituted phenyl and each of R⁸, R⁹, and R¹¹ is hydrogen, then R⁵and R⁶ cannot both be C₁ or OCH₃; provided that when X¹ and X² are bothCH and Ar is unsubstituted phenyl, then at least one of R⁵, R⁶, R⁸, R⁹,and R¹¹ is not hydrogen; provided that when X¹ is CH, X² is C—Cl, Ar isunsubstituted phenyl, and R¹¹ is Cl or O-isopropyl, then at least one ofR⁵, R⁶, R⁸, and R⁹ is not hydrogen; and provided that when Ar is1H-pyrazolo-1-yl, then Ar is not substituted with pyridin-3-yl andtrifluoromethyl.

In some embodiments, the compound is of formula II

where X¹ is selected from N and CR⁷; X² is selected from N and CR¹⁰;each of R¹, R², R³, and R⁴ is independently selected from —H, halogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈ alkenyl, substitutedor unsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A),—C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B),—NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A),—C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B),—NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; each of R⁸ and R⁹ is independently selectedfrom —H, halogen, —OR^(A), —NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B),—SH, and —SR^(A); each of R^(A), R^(B), and R^(C), when present, isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″,—NR′″C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; R′, R″, andR′″ are each independently hydrogen, unsubstituted C₁₋₄ alkyl, andsubstituted or unsubstituted C₃₋₆ cycloalkyl or R′ and R″ together withthe atoms which they substitute form a substituted or unsubstituted 5-,6-, or 7-membered ring; provided that when X¹ is N, X² is CH, and eachof R¹, R², R³, R⁴, R⁸, R⁹, and R¹¹ is hydrogen, then R⁵ and R⁶ cannotboth be C₁ or OCH₃; provided that when X¹ and X² are both CH, then atleast one of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, and R¹¹ is not hydrogen;and provided that when X¹ is CH, X² is C—Cl, and R¹¹ is Cl orO-isopropyl, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, and R⁹ isnot hydrogen.

In some embodiments, each of R¹, R², R³, and R⁴ is independentlyselected from —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₃-6 cycloalkyl, —C(O)NR^(A)R^(B), —OR^(A),—NR^(A)R^(B), substituted or unsubstituted 5- to 10-membered heteroaryl,and substituted or unsubstituted 3- to 10-membered heterocyclyl. In someembodiments, each of R¹, R², R³, and R⁴ is —H. In some embodiments, atleast one of R¹, R², R³, and R⁴ is halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl,—C(O)NR^(A)R^(B), —OR^(A), —NR^(A)R^(B), —S(O)₂R^(A), substituted orunsubstituted 5- to 10-membered heteroaryl, or substituted orunsubstituted 3- to 10-membered heterocyclyl. In some embodiments, R¹ isselected from —H, chloro, trifluoromethyl, cyclopropyl, —(C═O)NHCH₃,—OCH₃, —O-cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl-amino,and —OH; R² is selected from —H, chloro, and —OCH₃; R³ is selected from—H, chloro, cyclopropyl, —(C═O)NHCH₃, —OCH₃, —O-cyclopropyl,—NH-cyclopropyl, —S(O)₂-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl-amino,and —OH; and R⁴ is selected from —H, chloro, trifluoromethyl, and —OCH₃;wherein at least one of R¹, R², R³, and R⁴ is not —H.

In some embodiments, at least one of R¹ and R³ is selected from—S(O)₂-cyclopropyl and 1-methyl-piperazin-1-yl. In some embodiments, oneof R¹ and R³ is selected from —S(O)₂-cyclopropyl and1-methyl-piperazin-1-yl and the other of R¹ and R³ is selected from —H,—C₁, —S(O)₂-cyclopropyl, —NH-cyclopropyl, and cyclopropyl. In someembodiments, at least one of R¹ and R³ is —S(O)₂-cyclopropyl. In someembodiments, R¹ is —S(O)₂-cyclopropyl and R³ is —H. In some embodiments,at least one of R¹ and R³ is 1-methyl-piperazin-1-yl. In someembodiments, at least one of R¹ and R³ is piperazin-1-yl. In someembodiments, at least one of R¹ and R³ is —O-cyclopropyl and the otherof R¹ and R³ is —H. In some embodiments, each of R¹ and R³ is selectedfrom cyclopropyl, —O— cyclopropyl, —NH-cyclopropyl, —S(O)₂-cyclopropyl,1-methyl-piperazin-1-yl, piperazin-1-yl, and oxetan-3-yl.

In some embodiments, the compound is of formula III

where X¹ is selected from N and CR⁷; X² is selected from N and CR¹⁰;each of D¹, D², D³, and D⁴ is selected from CR¹, CR², CR³, CR⁴, N, O,and S; B is selected from C and N; each of R¹, R², R³, and R⁴ isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl,—CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A),—OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A),—C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B),—NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; each of R⁸ and R⁹ is independently selectedfrom —H, halogen, —OR^(A), —NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B),—SH, and —SR^(A); each of R^(A), R^(B), and R^(C), when present, isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″,—NR′″C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; R′, R″, andR′″ are each independently selected from —H, unsubstituted C₁₋₄ alkyl,and substituted or unsubstituted C₃₋₆ cycloalkyl or R′ and R″ togetherwith the atoms which they substitute form a substituted or unsubstituted5-, 6-, or 7-membered ring; provided that when B and D¹ are N, then D²and D⁴ cannot be C-pyridin-3-yl or C-trifluoromethyl.

In some embodiments, B is C. In some embodiments, each of D¹, D², and D⁴is CH and D³ is S. In some embodiments, each of D², D³, and D⁴ is CH andD¹ is S. In some embodiments, each of D¹, D³, and D⁴ is CH and D² is O.In some embodiments, each of D¹, D², and D³ is CH and D⁴ is O.

In some embodiments, X¹ is C—H. In some embodiments, X¹ is C—F. In someembodiments, X² is C—H. In some embodiments, X² is N. In someembodiments, R⁵ and R⁶ are both —H. In some embodiments, R⁵ is —CH₃ andR⁶ is —H. In some embodiments, each of R⁸ and R⁹ is independentlyselected from —H and halogen. In some embodiments, both R⁸ and R⁹ is —H.In some embodiments, R⁸ is fluoro and R⁹ is —H. In some embodiments, R¹¹is selected from —H, substituted or unsubstituted C₁₋₈ alkyl, and—NR^(A)R^(B). In some embodiments, R¹¹ is selected from —H, —CH₃, and—NH₂. In some embodiments, R¹¹ is —H. In some embodiments, R¹¹ is —CH₃.In some embodiments, R¹¹ is —NH₂. In some embodiments, X¹ is N and R⁷ isabsent.

In one aspect, a pharmaceutical composition having a compound of any oneof formulas I-III or any of the compounds disclosed herein and apharmaceutically acceptable carrier or excipient.

In another aspect, a method of treating an proliferative disorder in apatient in need thereof, includes administering a compound of any one offormulas I-II or any of the compounds disclosed herein or apharmaceutical composition disclosed herein to the patient. In someembodiments, proliferative disorder is cancer and is selected fromadrenal, anal, aplastic anemia, bile duct, bladder, bone, brain, breast,cervical, central nervous system, colon, endometrial, esophagial, ewingfamily, ocular, gallbladder, gastrointestinal carcinoid,gastrointestinal stromal, Kaposi sarcoma, kidney, laryngeal, leukemia,liver, lung, lymphomas, malignant mesothelioma, multiple myeloma,myelodysplastic syndrome, nasal cavity and paranasal sinus,nasopharyngeal, neuroblastoma, oral cavity and oropharyngeal,osteosarcoma, ovarian, pancreatic, penile, pituitary, prostate, rectal,retinoblastoma, rhabdomyosarcoma, salivary, sarcoma, skin, smallintestine, stomach, testicular, thymus, thyroid, uterine sarcoma,vaginal, and Wilms tumor cancers. In some embodiments, the proliferativedisorder is a gastric cancer. In some embodiments, the proliferativedisorder is selected from Castleman disease, gestational trophoblasticdisease, and Hodgkins disease.

DETAILED DESCRIPTION

While the terminology used in this application is standard within theart, the following definitions of certain terms are provided to assureclarity.

Units, prefixes, and symbols may be denoted in their SI accepted form.Numeric ranges recited herein are inclusive of the numbers defining therange and include and are supportive of each integer within the definedrange. Unless otherwise noted, the terms “a” or “an” are to be construedas meaning “at least one of.” The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin this application, including but not limited to patents, patentapplications, articles, books, and treatises, are hereby expresslyincorporated by reference in their entirety for any purpose.

The term “alkyl” refers to a saturated, branched or straight-chained orcyclic hydrocarbon radical (group) having from 1 to 16 carbon atomsincluding, but not limited to, saturated C₁-C₆ such as: methyl, ethyl,1-propyl and 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl,1,1-dimethylethyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,3,3-dimethyl-1-butyl, 3,3-dimethyl-2-butyl, 2-ethyl-1-butyl and thelike. Alkyl groups may be unsubstituted or substituted. Examples ofsuitable substituents include, but are not limited to amino, alkylamino,alkoxy, alkylsulfanyl, oxo (═O), halo, acyl, nitro, hydroxyl, cyano,aryl, alkylaryl, aryloxy, arylsulfanyl, arylamino, carbocyclyl,carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylthio, thione (═S), imino(═NR where R can be H, alkyl, acetyl, or aralkyl) and the like.

As used herein, “aralkyl” refers to an aryl group that is attached toanother moiety via an alkylene linker. Aralkyl groups can be optionallysubstituted with one or more substituents.

As used herein, “alkoxy” refers to an OR group, where R is alkyl(substituted or unsubstituted) or aryl. The term “lower alkoxy” refersalkoxy groups having one to six carbon atoms. Alkoxy groups can beoptionally substituted with one or more substituents.

As used herein, “alkylene” refers to an alkyl group or a cycloalkylgroup that has two points of attachment to two moieties (for example{—CH₂-} and {—CH₂CH₂-} etc.) where the brackets indicate points ofattachment. Alkylene groups may be optionally substituted with one moresubstituents.

As used herein, “aromatic ring” or “aryl” means a monocyclic orpolycyclic-aromatic ring or ring radical comprising carbon and hydrogenatoms. Typically, aryl groups have about 6 to about 14 carbon atom ringmembers. Examples of suitable aryl groups include, but are not limitedto, phenyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, aswell as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationto alkyl or alkyl substituted with one or more halo such astriflouormethyl or hydroxy), hydroxy, alkoxy, alkylsulfanyl, cyano,halo, amino, thiol, thioether, and nitro. In certain embodiments, thearyl group is a monocyclic ring, wherein the ring comprises 6 carbonatoms.

The term “arylalkyl” refers to alkyl substituted with aryl. The arylportion may be carbocyclic aryl (also referred to as carboaryl),heterocyclic aryl (also referred to as heteroaryl), or biaryl.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Alkylsulfanylgroups can be optionally substituted with one or more substituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom. Arylsulfanylgroups can be optionally substituted with one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be optionally substitutedwith one or more substituents. Examples of dialkenyl radicals include,but are not limited to, propandiene (allene), 1,3-butadiene,1,3-pentadiene, 1,4-pentadiene, 2-methyl-1,3-butadiene (isoprene),3-methyl-1,2-butadiene, 1,3-hexadiene, 1,4-hexadiene, 1,5-hexadiene,2,4-hexadiene, 2,3-dimethyl-1,3-butadiene, 2-methyl-1,3-pentadiene,2-methyl-1,4-pentadiene, 3-methyl-1,4-pentadiene,4-methyl-1,3-pentadiene, 3-methyl-1,3-pentadiene, and the like.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 7-octynyl,1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 5-decynyl,9-decynyl and the like. Alkynyl groups can be optionally substitutedwith one or more substituents.

As used herein, “cycloalkyl” means a saturated, mono- or polycyclicalkyl radical typically having from 3 to 14 carbon atoms. In someembodiments, the number of ring carbons is from 3 to 6. Representativecycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydro-naphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be optionally substituted with one or moresubstituents. Suitable substituents include halogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B),—OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl, where R^(A), R^(B), and R^(C) are furtherdefined here.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclo-hexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclone-nenyl, cyclo-nonadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be optionallysubstituted with one or more substituents.

As used herein, “ester” includes both ROCO— (in the case of R=alkyl,alkoxycarbonyl-) and RCOO— (in the case of R=alkyl, alkylcarbonyloxy-).

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic or polycyclic heterocyclic ring (typically having 3- to14-members) which is either a saturated ring or an unsaturatednon-aromatic ring. A 3-membered heterocycle can contain from 1 to 3heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 toabout 8 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized, oxygen, and sulfur, includingsulfoxide and sulfone.

The heterocycle may be attached via any heteroatom or carbon atom.Representative heterocycles include morpholinyl, thiomorpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. Furthermore, the heterocyclyl may be optionally substitutedwith one or more substituents (including without limitation to halo,alkyl, haloalkyl, aryl, hydroxyl, amino, alkylamino, dialkylamino,thiol, and alkoxy). Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in whichoursat least 1 ring member is a heteroatom selected from oxygen, sulfur andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment, the heteroaromatic ring system has a 7 to 14 ring membersand may contain from 1 to about 7 heteroatoms. Representativeheteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl,benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl,tetrazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl orbenzo(b)thienyl and the like. Heteroaryl groups may be optionallysubstituted with one or more substituents like heterocycle.

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR—, wherein R is H or a lower alkyl. Heteroalkyl groups can beoptionally substituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CH₂ICH₃,and the like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be optionally substitutedwith one or more substituents.

The term “fused” when used with aryl or heterocycle refers to the arylor heterocycle group sharing a common bond with another cyclic groupsuch as a phenyl ring.

The term “cancer” refers to a pathological diseases associated with thegrowth of transformed cells, and includes the pathological progressionof the disease. Thus the term includes cancers of all stages and of allcellular origin. Cancer cells have the capacity for autonomous growth(an abnormal state or condition characterized by rapidly proliferatingcell growth). The term is meant to include all types of cancerousgrowths or oncogenic processes, metastatic tissues or malignantlytransformed cells, tissues, or organs, irrespective of histopathologictype, or stage of invasiveness.

Examples of cancers include, but are not limited to, carcinoma andsarcoma such as leukemia, sarcomas, osteosarcoma, lymphomas, melanoma,ovarian cancer, skin cancer, testicular cancer, gastric cancer,pancreatic cancer, renal cancer, breast cancer, prostate cancer,colorectal cancer, cancer of the head and neck, brain cancer, esophagealcancer, bladder cancer, adrenal cortical cancer, lung cancer, bronchuscancer, endometrial cancer, nasopharyngeal cancer, cervical or hepaticcancer, or cancer of unknown primary site. In addition, cancer can beassociated with a drug resistance phenotype.

As used herein, a “patient” refers to one in need of treatment fordiseases and conditions affected by modulating epithelial-mesenchymaltransition or is afflicted within one or more of the diseases orconditions described herein or is at a recognized risk of developing oneor more of the diseases or conditions described herein as diagnosed byan attending physician or clinician. The identification of thosepatients who are in need of treatment for the conditions identifiedherein is well within the ability and knowledge of one skilled in theart. A clinician skilled in the art can readily identify, by the use ofclinical tests, physical examination and medical/family history, thosepatients who are in need of such treatment. A patient includes awarm-blooded animal such as a mammal which is in need of modulatedprotein kinase activity. It is understood that guinea pigs, dogs, cats,rats, mice, horses, cattle, sheep, and humans are examples of animalswithin the scope of the meaning of the term.

The terms “treatment,” “treating” and “treat,” as used herein, includetheir generally accepted meanings, i.e., the management and care of apatient for the purpose of preventing, reducing the risk in incurring ordeveloping a given condition or disease, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, delaying, or reversing theprogression or severity, and holding in check and/or treating existingcharacteristics, of a disease, disorder, or pathological condition,described herein, including the alleviation or relief of symptoms orcomplications, or the cure or elimination of the disease, disorder, orcondition. The present methods include both medical therapeutic and/orprophylactic treatment, as appropriate.

The terms “hydroxyl” and “hydroxy” both refer to an OH group.

In chemical structures where a carbon-carbon double bond exists (forexample olefins), the double bond may be trans (E), or c/s (Z).

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moiety, the identity of thesubstituent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety.

The compounds disclosed herein are defined by their chemical structuresand/or chemical names. Where a compound is referred to by both achemical structure and a chemical name, and the chemical structure andchemical name conflict, the chemical structure is determinative of thecompound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound. Examples ofsubstituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl include: analkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, anaryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, —C(O)NR′R″,—NR′″C(O)R″″, halo, —OR′″, cyano, nitro, haloalkoxy, —C(O)R′″, —NR′R″,—SR′″, —C(O)OR′″, —OC(O)R′″, —NR′″C(O)NR′R″, —OC(O)NR′R″, —NR′″C(O)OR″″,—S(O)_(p)R′″, or —S(O)_(p)NR′R″, wherein R′ and R″, for each occurrenceare, independently, H, an alkyl, a cycloalkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl; or R′ and R″ taken together with thenitrogen to which they are attached is a heterocyclyl or a heteroaryl;and R′″ and R″″ for each occurrence are, independently, H, an alkyl, acycloalkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of an alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R (where Ris —H, an alkyl, acetyl, or aralkyl).

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one or more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethylsilyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound otherwise disclosed herein. Prodrugs may only become activeupon such reaction under biological conditions, but they may haveactivity in their unreacted forms. Examples of prodrugs contemplated inthis invention include, but are not limited to, analogs or derivativesof compounds of any one of formulas I-III, or of Table 1 that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of compounds of any one offormulas I-III or of Table 1 that comprise —NO, —NO₂, —ONO, or —ONO₂moieties. Prodrugs can typically be prepared using well-known methods,such as those described by 1 Burger's Medicinal Chemistry and DrugDiscovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5^(th) ed), theentire teachings of which are incorporated herein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas I-III or of Table 1. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas I-III or of Table 1 having an acidicfunctional group, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxy ethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methyl-amine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas I-III or of Table 1having a basic functional group, such as an amino functional group, anda pharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude, but are not limited to, hydrogen sulfate, citric acid, aceticacid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide,nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylicacid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid,formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas I-III or ofTable 1. The term solvate includes hydrates (e.g., hemi-hydrate,mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.,diabetic retinopathy or other retinopathies), choroidalneovascularisation (e.g., macular degeneration), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, and desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In some embodiments, the proliferative disorder is cancer. Cancers thatcan be treated or prevented by the methods disclosed herein include, butare not limited to human sarcomas and carcinomas, e.g., fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Antiproliferative Compounds

The present disclosure addresses a need for effectiveanti-proliferative, anti-mitotic agents to directly treat cancers or toimprove the efficacy of other cancer treatments. The disclosure relatesto compounds and pharmaceutical compositions that are useful fortreating or preventing proliferative disorders, such as cancer.

In one embodiment, compounds of formula I are disclosed

that include pharmaceutically acceptable salts, solvates, and prodrugs,where Ar is an optionally substituted phenyl or optionally substituted5-membered heteroaryl ring, each having 0 to 5 substituents selectedfrom halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈alkynyl, —CN, —NO₂,—C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A),—OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B),—NR^(A)R^(B), —NR^(C)CO₂R^(A), —NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A),—S(O)₂R^(A), —S(O)₂NR^(A)R^(B), substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; providedthat when Ar is phenyl, at least one ortho-substitution is H.

X¹ is selected from N and CR⁷, and X² is selected from N and CR¹⁰

Each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ is independently selected from —H,halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈alkynyl, —CN, —NO₂,—C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A),—OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B),—NR^(A)R^(B), —NRCCO2RA, —NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A),—S(O)₂R^(A), —S(O)₂NR^(A)R^(B), substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

Each of R⁸ and R⁹ is independently selected from H, halogen, —OR^(A),—NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B), —SH, and —SR^(A).

Each of R^(A), R^(B), and R^(C), when present, is independently selectedfrom —H, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′,—OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″, —NR′″C(O)R′,—NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

Each of R′, R″, and R′″ are independently hydrogen, unsubstituted C₁₋₄alkyl, and substituted or unsubstituted C₃₋₆ cycloalkyl, or R′ and R″together with the atoms which they substitute form a substituted orunsubstituted 5-, 6-, or 7-membered ring.

In compounds of Formula I, the following exclusions may apply:

(1) when X¹ is N, X² is CH, and Ar is unsubstituted phenyl and each ofR⁸, R⁹, and R¹¹ is hydrogen, then R⁵ and R⁶ cannot both be C₁ or OCH₃;

(2) when X¹ and X² are both CH and Ar is unsubstituted phenyl, then atleast one of R⁵, R⁶, R⁸, R⁹, and R¹¹ is not hydrogen;

(3) when X¹ is CH, X² is C—Cl, Ar is unsubstituted phenyl, and R¹¹ is Clor O-isopropyl, then at least one of R⁵, R⁶, R⁸, and R⁹ is not hydrogen;

(4) when Ar isN-(5-(3-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl), X¹ is CH,and each of R⁵, R⁶, R⁷, R⁸, R⁹, and R¹¹ is not hydrogen;

(5) when Ar isN-(5-(3-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl), X¹ and X²are CH, and each of R⁵, R⁶, R⁸ and R⁹ are H, then R¹¹ is not —OCH₂CF₃,2-(pyrrolidin-1-yl)ethoxy, 2-morpholinoethoxy, orcyano; or alternativelyto (4) and (5) above, when Ar is 7H-pyrazolo-1-yl, then Ar is notsubstituted with pyridin-3-yl and trifluoromethyl; or alternatively toall of (1)-(5) above, one or more of the following compounds may beexcluded:

In another embodiment, compounds of formula II are disclosed

that include pharmaceutically acceptable salts, solvates, and prodrugs,where X¹ is selected from N and CR⁷, and X² is selected from N and CR¹⁰.

Each of R¹, R², R³, and R⁴ is independently selected from —H, halogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈ alkenyl, substitutedor unsubstituted C₂₋₈alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A),—C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B),—NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

Each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ is independently selected from —H,halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl,—CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A),—OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

Each of R⁸ and R⁹ is independently selected from —H, halogen, —OR^(A),—NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B), —SH, and —SR^(A).

Each of R^(A), R^(B), and R^(C), when present, is independently selectedfrom —H, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′,—OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″, —NR′″C(O)R′,—NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

R′, R″, and R′″ are each independently hydrogen, unsubstituted C₁₋₄alkyl, and substituted or unsubstituted C₃₋₆ cycloalkyl, or R′ and R″together with the atoms which they substitute form a substituted orunsubstituted 5-, 6-, or 7-membered ring.

In compounds of Formula II, the following exclusions apply:

(1) when X¹ is N, X² is CH, and each of R¹, R², R³, R⁴, R⁸, R⁹, and R¹¹is hydrogen, then R⁵ and R⁶ cannot both be C₁ or OCH₃;

(2) when X¹ and X² are both CH, then at least one of R¹, R², R³, R⁴, R⁵,R⁶, R⁸, R⁹, and R¹¹ is not hydrogen;

(3) when X¹ is CH, X² is C—Cl, and R¹¹ is Cl or O-isopropyl, then atleast one of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, and R⁹ is not hydrogen; oralternatively to (1)-(3) above, any one or more of the compoundsidentified as potential exceptions to formula I above.

In another embodiment, compounds of formula III are disclosed

that include pharmaceutically acceptable salts, solvates, and prodrugs,where X¹ is selected from N and CR⁷, and X² is selected from N and CR¹⁰.

Each of D¹, D², D³, and D⁴ is selected from CR¹, CR², CR³, CR⁴, N, O,and S. B is selected from C and N.

Each of R¹, R², R³, and R⁴ is independently selected from —H, halogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈ alkenyl, substitutedor unsubstituted C₂₋₈alkynyl, —CN, —NO₂, —C(O)R^(A), —CO₂R^(A),—C(O)NR^(A)R^(B), —OR^(A), —OC(O)R^(A), —OC(O)NR^(A)R^(B),—NR^(C)C(O)R^(A), —NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

Each of R⁵, R⁶, R⁷, R¹⁰, and R¹¹ is independently selected from —H,halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl,—CN, —NO₂, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B), —OR^(A),—OC(O)R^(A), —OC(O)NR^(A)R^(B), —NR^(C)C(O)R^(A),—NR^(C)C(O)NR^(A)R^(B), —NR^(A)R^(B), —NR^(C)CO₂R^(A),—NR^(C)S(O)₂R^(A), —SR^(A), —S(O)R^(A), —S(O)₂R^(A), —S(O)₂NR^(A)R^(B),substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

Each of R⁸ and R⁹ is independently selected from H, halogen, —OR^(A),—NH₂, —NO₂, —O(CO)R^(A), —O(CO)NR^(A)R^(B), —SH, and —SR^(A).

Each of R^(A), R^(B), and R^(C), when present, is independently selectedfrom —H, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′,—OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″, —NR′″C(O)R′,—NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

R′, R″, and R′″ are each independently hydrogen, unsubstituted C₁₋₄alkyl, and substituted or unsubstituted C₁₋₆ cycloalkyl or R′ and R″together with the atoms which they substitute form a substituted orunsubstituted 5-, 6-, or 7-membered ring.

In compounds of Formula III, the following exclusions apply: (1) when Band D¹ are N, D² is C-3-pyridyl, D³ is CH, and D⁴ is C(CF₃), X¹ is CH,and each of R⁵, R⁶, R⁸, R⁹, R¹¹ are H, then X² is not N; and (2) when Band D¹ are N, D² is C-3-pyridyl, D³ is CH, and D⁴ is C(CF₃), X¹ and X²are CH, and each of R², R³, R⁶, R⁷ are H, then R⁵ is not OCH₂CF₃,2-(pyrrolidin-1-yl)ethoxy, 2-morpholinoethoxy, orcyano;

or alternatively to (1) and (2) above, when B and D¹ are N, then D² andD⁴ cannot be C-pyridin-3-yl or C-trifluoromethyl.

or alternatively to (1) and (2) above, any one or more of the compoundsidentified above with respect to formula I above.

In some embodiments of the compounds represented by formulas I-III, X¹is CR⁷. In some embodiments, X¹ is C—H. In some embodiment, X¹ is N. Insome embodiments, X¹ is C—F. In some embodiments, X² is CR¹⁰. In someembodiments, X² is C—H. In some embodiment, X² is N. In someembodiments, X¹ is CR⁷ and X² is CR¹⁰. In some embodiments, X¹ and X²are both C—H. In some embodiments, X¹ and X² are both N. In someembodiments, X¹ is CR⁷ and X² is N. In some embodiments, X¹ is N and X²is CR¹⁰. In some embodiments, X¹ is CH and X² is N. In some embodiments,X¹ is C—H and X² is N. In some embodiments, X¹ is C—F and X² is N. Insome embodiments, X¹ is N and R⁷ is absent.

In some embodiments of compounds represented by formula III, B is C. Insome embodiments, B is N.

In some embodiments of compounds represented by formula III, D¹ is CR¹.In some embodiments, D¹ is N. In some embodiments, D¹ is O. In someembodiments, D¹ is S.

In some embodiments of compounds represented by formula III, D² is CR².In some embodiments, D² is N. In some embodiments, D² is O. In someembodiments, D² is S.

In some embodiments of compounds represented by formula III, D³ is CR³.In some embodiments, D³ is N. In some embodiments, D³ is O. In someembodiments, D³ is S.

In some embodiments of compounds represented by formula III, D⁴ is CR⁴.In some embodiments, D⁴ is N. In some embodiments, D⁴ is O. In someembodiments, D⁴ is S.

In some embodiments of compounds represented by formula III, each of D¹,D², and D⁴ is CH and D³ is S. In some embodiments, each of D², D³, andD⁴ is CH and D¹ is S. In some embodiments, each of D¹, D³, and D⁴ is CHand D² is O. In some embodiments, each of D¹, D², and D³ is CH and D⁴ isO.

In some embodiments of the compounds represented by formulas II and III,R¹ is H. In some embodiments, R¹ is halogen. In some embodiments, R¹ issubstituted or unsubstituted C₁₋₈ alkyl. In some embodiments, R¹ isunsubstituted C₁₋₈ alkyl. In some embodiments, R¹ is substituted C₁₋₈alkyl. In some embodiments, R¹ is cycloalkyl. In some embodiments, R¹ iscyclopropyl. In some embodiments, R¹ is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R¹ is substituted C₃₋₆ cycloalkyl.In some embodiments, R¹ is unsubstituted C₃₋₆ cycloalkyl. In someembodiments, R¹ is substituted or unsubstituted C₂₋₈ alkenyl. In someembodiments, R¹ is unsubstituted C₂₋₈ alkenyl. In some embodiments, R¹is substituted C₂₋₈ alkenyl. In some embodiments, R¹ is substituted orunsubstituted C₂₋₈alkynyl. In some embodiments, R¹ is unsubstitutedC₂₋₈alkynyl. In some embodiments, R¹ is substituted C₂₋₈alkynyl. In someembodiments, R¹ is —CN. In some embodiments, R¹ is —NO₂. In someembodiments, R¹ is —C(O)R^(A). In some embodiments, R¹ is —CO₂R^(A). Insome embodiments, R¹ is —C(O)NR^(A)R^(B). In some embodiments, R¹ is—OR^(A). In some embodiments, R¹ is —OC(O)R^(A). In some embodiments, R¹is —OC(O)NR^(A)R^(B). In some embodiments, R¹ is —NR^(C)C(O)R^(A). Insome embodiments, R¹ is —R^(C)C(O) NR^(A)R^(B). In some embodiments, R¹is —NR^(A)R^(B). In some embodiments, R¹ is —NR^(C)CO₂R^(A). In someembodiments, R¹ is —NR^(C)S(O)₂R^(A). In some embodiments, R¹ is—SR^(A). In some embodiments, R¹ is —S(O)R^(A). In some embodiments, R¹is —S(O)₂R^(A) In some embodiments, R¹ is —S(O)₂NR^(A)R^(B). In someembodiments, R¹ is substituted or unsubstituted C₆₋₁₀ aryl. In someembodiments, R¹ is substituted C₆₋₁₀ aryl. In some embodiments, R¹ isunsubstituted C₆₋₁₀ aryl. In some embodiments, R¹ is substituted orunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R¹ issubstituted 5- to 10-membered heteroaryl. In some embodiments, R¹ isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R¹ issubstituted or unsubstituted 3- to 10-membered heterocyclyl. In someembodiments, R¹ is substituted 3- to 10-membered heterocyclyl. In someembodiments, R¹ is unsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R¹is selected from: —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₃₋₆ cycloalkyl, —C(O)NR^(A)R^(B), —OR^(A),—NR^(A)R^(B), —S(O)₂R^(A), substituted or unsubstituted 5- to10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R¹is selected from: —H, chloro, trifluoromethyl, cyclopropyl, —C═O)NHCH₃,—OCH₃, —O-cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazinyl-1-yl,pyrrolidinyl-3-yl-amino, and —OH. In some embodiments, R¹ is —H. In someembodiments, R¹ is chloro. In some embodiments, R¹ is trifluoromethyl.In some embodiments, R¹ is cyclopropyl. In some embodiments, R¹ is—(C═O)NHCH₃. In some embodiments, R¹ is —OCH₃. In some embodiments, R¹is —O-cyclopropyl. In some embodiments, R¹ is —NH— cyclopropyl. In someembodiments, R¹ is 1-methyl-piperazin-1-yl. In some embodiments, R¹ is4-methylpiperazin-1-yl)ethoxyl. In some embodiments, R¹ is phenyl. Insome embodiments, R¹ is oxetan-3-yl. In some embodiments, R¹ iscyclobutyl. In some embodiments, R¹ is and tert-butyl. In someembodiments, R¹ is —S(O)₂-cyclopropyl. In some embodiments, R¹ ispiperazinyl-1-yl. In some embodiments, R¹ is pyrrolidiny-3-yl-amino. Insome embodiments, R¹ is —OH.

In some embodiments of compounds represented by formulas II and III, R²is —H. In some embodiments, R² is halogen. In some embodiments, R² issubstituted or unsubstituted C₁₋₈ alkyl. In some embodiments, R² iscycloalkyl. In some embodiments, R² is cyclopropyl. In some embodiments,R² is substituted or unsubstituted C₃₋₆ cycloalkyl. In some embodiments,R² is substituted C₃₋₆ cycloalkyl. In some embodiments, R² isunsubstituted C₃₋₆ cycloalkyl. In some embodiments, R² is unsubstitutedC₁₋₈ alkyl. In some embodiments, R² is substituted C₁₋₈ alkyl. In someembodiments, R² is substituted or unsubstituted C₂₋₈ alkenyl. In someembodiments, R² is unsubstituted C₂₋₈ alkenyl. In some embodiments, R²is substituted C₂₋₈ alkenyl. In some embodiments, R² is substituted orunsubstituted C₂₋₈alkynyl. In some embodiments, R² is unsubstitutedC₂₋₈alkynyl. In some embodiments, R² is substituted C₂₋₈alkynyl. In someembodiments, R² is —CN. In some embodiments, R² is —NO₂. In someembodiments, R² is —C(O)R^(A). In some embodiments, R² is —CO₂R^(A). Insome embodiments, R² is —C(O)NR^(A)R^(B). In some embodiments, R² is—OR^(A). In some embodiments, R² is —OC(O)R^(A). In some embodiments, R²is —OC(O)NR^(A)R^(B). In some embodiments, R² is —NR^(C)C(O)R^(A). Insome embodiments, R² is —R^(C)C(O) NR^(A)R^(B). In some embodiments, R²is —NR^(A)R^(B). In some embodiments, R² is —NR^(C)CO₂R^(A). In someembodiments, R² is —NR^(C)S(O)₂R^(A). In some embodiments, R² is—SR^(A). In some embodiments, R² is —S(O)R^(A). In some embodiments, R²is —S(O)₂R^(A). In some embodiments, R² is —S(O)₂NR^(A)R^(B). In someembodiments, R² is substituted or unsubstituted C₆₋₁₀ aryl. In someembodiments, R² is substituted C₆₋₁₀ aryl. In some embodiments, R² isunsubstituted C₆₋₁₀ aryl. In some embodiments, R² is substituted orunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R² issubstituted 5- to 10-membered heteroaryl. In some embodiments, R² isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R² issubstituted or unsubstituted 3- to 10-membered heterocyclyl. In someembodiments, R² is substituted 3- to 10-membered heterocyclyl. In someembodiments, R² is unsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R²is selected from: —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₃₋₆ cycloalkyl, —C(O)NR^(A)R^(B), —OR^(A),—NR^(A)R^(B), —S(O)₂R^(A), substituted or unsubstituted 5- to10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R²is selected from: —H, chloro, trifluoromethyl, cyclopropyl, —C═O)NHCH₃,—OCH₃, —O-cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazinyl-1-yl,pyrrolidiny-3-yl-amino, and —OH. In some embodiments, R² is —H. In someembodiments, R² is chloro. In some embodiments, R² is trifluoromethyl.In some embodiments, R² is cyclopropyl. In some embodiments, R² is—(C═O)NHCH₃. In some embodiments, R² is —OCH₃. In some embodiments, R²is —O-cyclopropyl. In some embodiments, R² is —NH— cyclopropyl. In someembodiments, R² is 1-methyl-piperazin-1-yl. In some embodiments, R² is4-methylpiperazin-1-yl)ethoxyl. In some embodiments, R² is phenyl. Insome embodiments, R² is oxetan-3-yl. In some embodiments, R² iscyclobutyl. In some embodiments, R² is and tert-butyl. In someembodiments, R² is chloro or —OCH₃. In some embodiments, R² is—S(O)₂-cyclopropyl. In some embodiments, R² is piperazin-1-yl. In someembodiments, R² is pyrrolidin-3-yl-amino. In some embodiments, R² is—OH.

In some embodiments of compounds represented by formulas II and III, R³is H. In some embodiments, R³ is halogen. In some embodiments, R³ issubstituted or unsubstituted C₁₋₈ alkyl. In some embodiments, R³ isunsubstituted C₁₋₈ alkyl. In some embodiments, R³ is substituted C₁₋₈alkyl. In some embodiments, R³ is cycloalkyl. In some embodiments, R³ iscyclopropyl. In some embodiments, R³ is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R³ is substituted C₃₋₆ cycloalkyl.In some embodiments, R³ is unsubstituted C₃₋₆ cycloalkyl. In someembodiments, R³ is substituted or unsubstituted C₂₋₈ alkenyl. In someembodiments, R³ is unsubstituted C₂₋₈ alkenyl. In some embodiments, R³is substituted C₂₋₈ alkenyl. In some embodiments, R³ is substituted orunsubstituted C₂₋₈alkynyl. In some embodiments, R³ is unsubstituted C₂₋₈alkynyl. In some embodiments, R³ is substituted C₂₋₈alkynyl. In someembodiments, R³ is —CN. In some embodiments, R³ is —NO₂. In someembodiments, R³ is —C(O)R^(A). In some embodiments, R³ is —CO₂R^(A). Insome embodiments, R³ is —C(O)NR^(A)R^(B). In some embodiments, R³ is—OR^(A). In some embodiments, R³ is —OC(O)R^(A). In some embodiments, R³is —OC(O)NR^(A)R^(B). In some embodiments, R³ is —NR^(C)C(O)R^(A). Insome embodiments, R³ is —R^(C)C(O)NR^(A)R^(B). In some embodiments, R³is —NR^(A)R^(B). In some embodiments, R³ is —NR^(C)CO₂R^(A) In someembodiments, R³ is —NR^(C)S(O)₂R^(A) In some embodiments, R³ is —SR^(A).In some embodiments, R³ is —S(O)R^(A). In some embodiments, R³ is—S(O)₂R^(A). In some embodiments, R³ is —S(O)₂NR^(A)R^(B). In someembodiments, R³ is substituted or unsubstituted C₆₋₁₀ aryl. In someembodiments, R³ is substituted C₆₋₁₀ aryl. In some embodiments, R³ isunsubstituted C₆₋₁₀ aryl. In some embodiments, R³ is substituted orunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R³ issubstituted 5- to 10-membered heteroaryl. In some embodiments, R³ isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R³ issubstituted or unsubstituted 3- to 10-membered heterocyclyl. In someembodiments, R³ is substituted 3- to 10-membered heterocyclyl. In someembodiments, R³ is unsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R³is selected from: —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₃₋₆ cycloalkyl, —C(O)NR^(A)R^(B), —OR^(A),—NR^(A)R^(B), —S(O)₂R^(A), substituted or unsubstituted 5- to10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R³is selected from: —H, chloro, trifluoromethyl, cyclopropyl, —C═O)NHCH₃,—OCH₃, —O— cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methyl-piperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl, and—OH. In some embodiments, R³ is chloro. In some embodiments, R³ iscyclopropyl. In some embodiments, R³ is —(C═O)NHCH₃. In someembodiments, R³ is —OCH₃. In some embodiments, R³ is —O-cyclopropyl. Insome embodiments, R³ is —NH— cyclopropyl. In some embodiments, R³ is1-methyl-piperazin-1-yl. In some embodiments, R³ is4-methylpiperazin-1-yl)ethoxyl. In some embodiments, R³ is phenyl. Insome embodiments, R³ is oxetan-3-yl. In some embodiments, R³ iscyclobutyl. In some embodiments, R³ is and tert-butyl. In someembodiments, R³ is —S(O)₂-cyclopropyl. In some embodiments, R³ ispiperazin-1-yl. In some embodiments, R³ is pyrrolidin-3-yl. In someembodiments, R³ is —OH.

In some embodiments of compounds represented by formulas II and III, R⁴is H. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ issubstituted or unsubstituted C₁₋₈ alkyl. In some embodiments, R⁴ isunsubstituted C₁₋₈ alkyl. In some embodiments, R⁴ is substituted C₁₋₈alkyl. In some embodiments, R⁴ is cycloalkyl. In some embodiments, R⁴ iscyclopropyl. In some embodiments, R⁴ is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R⁴ is substituted C₃₋₆ cycloalkyl.In some embodiments, R⁴ is unsubstituted C₃₋₆ cycloalkyl. In someembodiments, R⁴ is substituted or unsubstituted C₂₋₈ alkenyl. In someembodiments, R⁴ is unsubstituted C₂₋₈ alkenyl. In some embodiments, R⁴is substituted C₂₋₈ alkenyl. In some embodiments, R⁴ is substituted orunsubstituted C₂₋₈ alkynyl. In some embodiments, R⁴ is unsubstitutedC₂₋₈alkynyl. In some embodiments, R⁴ is substituted C₂₋₈ alkynyl. Insome embodiments, R⁴ is —CN. In some embodiments, R⁴ is —NO₂. In someembodiments, R⁴ is —C(O)R^(A). In some embodiments, R⁴ is —CO₂R^(A). Insome embodiments, R⁴ is —C(O)NR^(A)R^(B). In some embodiments, R⁴ is—OR^(A). In some embodiments, R⁴ is —OC(O)R^(A). In some embodiments, R⁴is —OC(O)NR^(A)R^(B). In some embodiments, R⁴ is —NR^(C)C(O)R^(A). Insome embodiments, R⁴ is —R^(C)C(O)NR^(A)R^(B). In some embodiments, R⁴is —NR^(A)R^(B). In some embodiments, R⁴ is —NR^(C)CO₂R^(A). In someembodiments, R⁴ is —NR^(C)S(O)₂R^(A). In some embodiments, R⁴ is—SR^(A). In some embodiments, R⁴ is —S(O)R^(A). In some embodiments, R⁴is —S(O)₂R^(A). In some embodiments, R⁴ is —S(O)₂NR^(A)R^(B). In someembodiments, R⁴ is substituted or unsubstituted C₆₋₁₀ aryl. In someembodiments, R⁴ is substituted C₆₋₁₀ aryl. In some embodiments, R⁴ isunsubstituted C₆₋₁₀ aryl. In some embodiments, R⁴ is substituted orunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R⁴ issubstituted 5- to 10-membered heteroaryl. In some embodiments, R⁴ isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R⁴ issubstituted or unsubstituted 3- to 10-membered heterocyclyl. In someembodiments, R⁴ is substituted 3- to 10-membered heterocyclyl. In someembodiments, R⁴ is unsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R⁴is selected from: —H, halogen, substituted or unsubstituted C₁₋₈ alkyl,cycloalkyl, —C(O)NR^(A)R^(B), —OR^(A), —NR^(A)R^(B), —S(O)₂R^(A),substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R⁴is selected from: —H, chloro, trifluoromethyl, cyclopropyl, —C═O)NHCH₃,—OCH₃, —O-cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl-amino,and —OH. In some embodiments, R⁴ is —H. In some embodiments, R⁴ ischloro. In some embodiments, R⁴ is trifluoromethyl. In some embodiments,R⁴ is cyclopropyl. In some embodiments, R⁴ is —(C═O)NHCH₃. In someembodiments, R⁴ is —OCH₃. In some embodiments, R⁴ is —O-cyclopropyl. Insome embodiments, R⁴ is —NH— cyclopropyl. In some embodiments, R⁴ is1-methyl-piperazin-1-yl. In some embodiments, R⁴ is4-methylpiperazin-1-yl)ethoxyl. In some embodiments, R⁴ is phenyl. Insome embodiments, R⁴ is oxetan-3-yl. In some embodiments, R⁴ iscyclobutyl. In some embodiments, R⁴ is and tert-butyl. In someembodiments, R⁴ is chloro trifluoromethyl, or —OCH₃. In someembodiments, R⁴ is —S(O)₂-cyclopropyl. In some embodiments, R⁴ ispiperazin-1-yl. In some embodiments, R⁴ is pyrrolidin-3-yl. In someembodiments, R⁴ is —OH.

In some embodiments of compounds represented by formulas II and III,each of R¹, R², R³, and R⁴ is —H. In some embodiments represented byformula II, at least one of R¹, R², R³, and R⁴ is not —H.

In some embodiments of Formula II, at least one of R¹, R², R³, and R⁴ ishalogen, substituted or unsubstituted C₁₋₈ alkyl, cycloalkyl,—C(O)NR^(A)R^(B), —OR^(A), —NR^(A)R^(B), —S(O)₂R^(A), substituted orunsubstituted 5- to 10-membered heteroaryl, or substituted orunsubstituted 3- to 10-membered heterocyclyl.

In some embodiments of compounds represented by formulas II and III, R¹is selected from —H, chloro, trifluoromethyl, cyclopropyl, —(C═O)NHCH₃,—OCH₃, —O— cyclopropyl, —NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl-amino,and —OH; R² is selected from —H, chloro and —OCH₃; R³ is selected fromchloro, cyclopropyl, —(C═O)NHCH₃, —OCH₃, —O-cyclopropyl,—NH-cyclopropyl, 1-methyl-piperazin-1-yl,4-methylpiperazin-1-yl)ethoxyl, phenyl, oxetan-3-yl, cyclobutyl,tert-butyl, —S(O)₂-cyclopropyl, piperazin-1-yl, pyrrolidin-3-yl-amino,and —OH; and R⁴ is selected from —H, chloro, trifluoromethyl, and —OCH₃,wherein at least one of R¹, R², R³, and R⁴ is not —H.

In some embodiments, at least one of R¹ and R³ is selected from—S(O)₂-cyclopropyl and 1-methyl-piperazin-1-yl. In some embodiments, oneof R¹ and R³ is selected from —S(O)₂-cyclopropyl and1-methyl-piperazin-1-yl and the other of R¹ and R³ is selected from —H,—C₁, —S(O)₂-cyclopropyl, —NH-cyclopropyl, and cyclopropyl. In someembodiments, at least one of R¹ and R³ is —S(O)₂-cyclopropyl. In someembodiments, R¹ is —S(O)₂-cyclopropyl and R³ is —H. In some embodiments,at least one of R¹ and R³ is 1-methyl-piperazin-1-yl. In someembodiments, at least one of R¹ and R³ is piperazin-1-yl. In someembodiments, at least one of R¹ and R³ is —O-cyclopropyl and the otherof R¹ and R³ is —H. In some embodiments, each of R¹ and R³ is selectedfrom cyclopropyl, —O— cyclopropyl, —NH-cyclopropyl, —S(O)₂-cyclopropyl,1-methyl-piperazin-1-yl, piperazin-1-yl, and oxetan-3-yl.

In some embodiments of compounds of Formula I-III, R⁵ is H. In someembodiments of compounds of Formula I-III, R⁶ is H. In some embodimentsof compounds of Formula I-III, R⁵ and R⁶ are both H.

In some embodiments of compounds of Formula I-III, R⁷ is H.

In some embodiments of compounds of Formula I-III, R⁸ is selected from—H and halogen. In some embodiments, R⁸ is —H. In some embodiments, R⁸is halogen. In some embodiments, R⁸ is fluoro. In some embodiments, R⁸is chloro. In some embodiments, R⁸ is bromo. In some embodiments, R⁸ isiodo.

In some embodiments of compounds of Formula I-III, R⁹ is selected from—H and halogen. In some embodiments, R⁹ is —H. In some embodiments, R⁹is halogen. In some embodiments, R⁹ is fluoro. In some embodiments, R⁹is chloro. In some embodiments, R⁹ is bromo. In some embodiments, R⁹ isiodo.

In some embodiments of compounds of Formula I-III, R⁸ and R⁸ are both—H. In some embodiments, R⁸ is fluoro and R⁹ is —H.

In some embodiments of compounds of Formula I-III, R¹⁰ is H.

In some embodiments of compounds of Formula I-III, R¹¹ is selected from—H, substituted or unsubstituted C₁₋₈ alkyl, cycloalkyl, and—NR^(A)R^(B). In some embodiments, R¹¹ is —H. In some embodiments, R¹¹is substituted or unsubstituted C₁₋₈ alkyl. In some embodiments, R¹¹ issubstituted C₁₋₈ alkyl. In some embodiments, R¹¹ is substituted C₁₋₈alkyl. In some embodiments, R¹¹ is cycloalkyl. In some embodiments, R¹¹is —NR^(A)R^(B).

In some embodiments of compounds of Formula I-III, R¹¹ is selected from—H, —CH₃, and —NH₂. In some embodiments, R¹¹ is —H. In some embodiments,R¹¹ is —CH₃. In some embodiments, R¹¹ is —NH₂.

In some embodiments of compounds of Formula I-III, R^(A) is —H. In someembodiments, R^(A) is halogen. In some embodiments, R^(A) is substitutedor unsubstituted C₁₋₈ alkyl. In some embodiments, R^(A) is unsubstitutedC₁₋₈ alkyl. In some embodiments, R^(A) is substituted C₁₋₈ alkyl. Insome embodiments, R^(A) is cycloalkyl. In some embodiments, R^(A) iscyclopropyl. In some embodiments, R^(A) is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R^(A) is substituted C₃₋₆cycloalkyl. In some embodiments, R^(A) is unsubstituted C₃₋₆ cycloalkyl.In some embodiments, R^(A) is substituted or unsubstituted C₂₋₈ alkenyl.In some embodiments, R^(A) is unsubstituted C₂₋₈ alkenyl. In someembodiments, R^(A) is substituted C₂₋₈ alkenyl. In some embodiments,R^(A) is substituted or unsubstituted C₂₋₈ alkynyl. In some embodiments,R^(A) is unsubstituted C₂₋₈ alkynyl. In some embodiments, R^(A) issubstituted C₂₋₈ alkynyl. In some embodiments, R^(A) is —CN. In someembodiments, R^(A) is ═O. In some embodiments, R^(A) is —NO₂. In someembodiments, R^(A) is —OR′. In some embodiments, R^(A) is —OC(O)R′. Insome embodiments, R^(A) is —CO₂R′. In some embodiments, R^(A) is—C(O)R′. In some embodiments, R^(A) is —C(O)NR′R″. In some embodiments,R^(A) is —OC(O)NR′R″. In some embodiments, R^(A) is —NR′″C(O)R′. In someembodiments, R^(A) is —NR′″C(O)NR′R″. In some embodiments, R^(A) is—NR′R″. In some embodiments, R^(A) is —NR′″CO₂R′. In some embodiments,R^(A) is —SR′. In some embodiments, R^(A) is-S(O)R′. In someembodiments, R^(A) is —S(O)₂R′. In some embodiments, R^(A) is—S(O)₂-cycloalkyl. In some embodiments, R^(A) is —S(O)₂-cyclopropyl. Insome embodiments, R^(A) is substituted or unsubstituted—S(O)₂-cycloalkyl. In some embodiments, R^(A) is substituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(A) is unsubstituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(A) is —S(O)₂NR′R″. In someembodiments, R^(A) is —NR'S(O)₂R″. In some embodiments, R^(A) issubstituted or unsubstituted C₆₋₁₀ aryl. In some embodiments, R^(A) isunsubstituted C₆₋₁₀ aryl. In some embodiments, R^(A) is substitutedC₆₋₁₀ aryl. In some embodiments, R^(A) is substituted or unsubstituted5- to 10-membered heteroaryl. In some embodiments, R^(A) isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^(A)is substituted 5- to 10-membered heteroaryl. In some embodiments, R^(A)is and substituted or unsubstituted 3- to 10-membered heterocyclyl. Insome embodiments, R^(A) is unsubstituted 3- to 10-membered heterocyclyl.In some embodiments, R^(A) is substituted 3- to 10-memberedheterocyclyl.

In some embodiments of compounds of Formula I-III, R^(B) is —H. In someembodiments, R^(B) is halogen. In some embodiments, R^(B) is substitutedor unsubstituted C₁₋₈ alkyl. In some embodiments, R^(B) is unsubstitutedC₁₋₈ alkyl. In some embodiments, R^(B) is substituted C₁₋₈ alkyl. Insome embodiments, R^(B) is cycloalkyl. In some embodiments, R^(B) iscyclopropyl. In some embodiments, R^(B) is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R^(B) is substituted C₃₋₆cycloalkyl. In some embodiments, R^(B) is unsubstituted C₃₋₆ cycloalkyl.In some embodiments, R^(B) is substituted or unsubstituted C₂₋₈ alkenyl.In some embodiments, R^(B) is unsubstituted C₂₋₈ alkenyl. In someembodiments, R^(B) is substituted C₂₋₈ alkenyl. In some embodiments,R^(B) is substituted or unsubstituted C₂₋₈ alkynyl. In some embodiments,R^(B) is unsubstituted C₂₋₈ alkynyl. In some embodiments, R^(B) issubstituted C₂₋₈ alkynyl. In some embodiments, R^(B) is —CN. In someembodiments, R^(B) is ═O. In some embodiments, R^(B) is —NO₂. In someembodiments, R^(B) is —OR′. In some embodiments, R^(B) is —OC(O)R′. Insome embodiments, R^(B) is —CO₂R′. In some embodiments, R^(B) is—C(O)R′. In some embodiments, R^(B) is —C(O)NR′R″. In some embodiments,R^(B) is —OC(O)NR′R″. In some embodiments, R^(B) is —NR′″C(O)R′. In someembodiments, R^(B) is —NR′″C(O)NR′R″. In some embodiments, R^(B) is—NR′R″. In some embodiments, R^(B) is —NR′″CO₂R′. In some embodiments,R^(B) is —SR′. In some embodiments, R^(B) is-S(O)R′. In someembodiments, R^(B) is —S(O)₂R′. In some embodiments, R^(B) is—S(O)₂-cycloalkyl. In some embodiments, R^(B) is —S(O)₂-cyclopropyl. Insome embodiments, R^(B) is substituted or unsubstituted—S(O)₂-cycloalkyl. In some embodiments, R^(B) is substituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(B) is unsubstituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(B) is —S(O)₂NR′R″. In someembodiments, R^(B) is —NR'S(O)₂R″. In some embodiments, R^(B) issubstituted or unsubstituted C₆₋₁₀ aryl. In some embodiments, R^(B) isunsubstituted C₆₋₁₀ aryl. In some embodiments, R^(B) is substitutedC₆₋₁₀ aryl. In some embodiments, R^(B) is substituted or unsubstituted5- to 10-membered heteroaryl. In some embodiments, R^(B) isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^(B)is substituted 5- to 10-membered heteroaryl. In some embodiments, R^(B)is and substituted or unsubstituted 3- to 10-membered heterocyclyl. Insome embodiments, R^(B) is unsubstituted 3- to 10-membered heterocyclyl.In some embodiments, R^(B) is substituted 3- to 10-memberedheterocyclyl.

In some embodiments of compounds of Formula I-III, R^(C) is —H. In someembodiments, R^(C) is halogen. In some embodiments, R^(C) is substitutedor unsubstituted C₁₋₈ alkyl. In some embodiments, R^(C) is unsubstitutedC₁₋₈ alkyl. In some embodiments, R^(C) is substituted C₁₋₈ alkyl. Insome embodiments, R^(C) is cycloalkyl. In some embodiments, R^(C) iscyclopropyl. In some embodiments, R^(C) is substituted or unsubstitutedC₃₋₆ cycloalkyl. In some embodiments, R^(C) is substituted C₃₋₆cycloalkyl. In some embodiments, R^(C) is unsubstituted C₃₋₆ cycloalkyl.In some embodiments, R^(C) is substituted or unsubstituted C₂₋₈ alkenyl.In some embodiments, R^(C) is unsubstituted C₂₋₈ alkenyl. In someembodiments, R^(C) is substituted C₂₋₈ alkenyl. In some embodiments,R^(C) is substituted or unsubstituted C₂₋₈ alkynyl. In some embodiments,R^(C) is unsubstituted C₂₋₈ alkynyl. In some embodiments, R^(C) issubstituted C₂₋₈ alkynyl. In some embodiments, R^(C) is —CN. In someembodiments, R^(C) is ═O. In some embodiments, R^(C) is —NO₂. In someembodiments, R^(B) is —OR′. In some embodiments, R^(C) is —OC(O)R′. Insome embodiments, R^(C) is —CO₂R′. In some embodiments, R^(C) is—C(O)R′. In some embodiments, R^(C) is —C(O)NR′R″. In some embodiments,R^(C) is —OC(O)NR′R″. In some embodiments, R^(C) is —NR′″C(O)R′. In someembodiments, R^(C) is —NR′″C(O)NR′R″. In some embodiments, R^(C) is—NR′R″. In some embodiments, R^(C) is —NR′″CO₂R′. In some embodiments,R^(C) is —SR′. In some embodiments, R^(C) is-S(O)R′. In someembodiments, R^(C) is —S(O)₂R′. In some embodiments, R^(C) is—S(O)₂-cycloalkyl. In some embodiments, R^(C) is —S(O)₂-cyclopropyl. Insome embodiments, R^(C) is substituted or unsubstituted—S(O)₂-cycloalkyl. In some embodiments, R^(C) is substituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(C) is unsubstituted —S(O)₂—C₃₋₆cycloalkyl. In some embodiments, R^(C) is —S(O)₂NR′R″. In someembodiments, R^(C) is —NR'S(O)₂R″. In some embodiments, R^(C) issubstituted or unsubstituted C₆₋₁₀ aryl. In some embodiments, R^(C) isunsubstituted C₆₋₁₀ aryl. In some embodiments, R^(C) is substitutedC₆₋₁₀ aryl. In some embodiments, R^(C) is substituted or unsubstituted5- to 10-membered heteroaryl. In some embodiments, R^(C) isunsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^(C)is substituted 5- to 10-membered heteroaryl. In some embodiments, R^(C)is and substituted or unsubstituted 3- to 10-membered heterocyclyl. Insome embodiments, R^(C) is unsubstituted 3- to 10-membered heterocyclyl.In some embodiments, R^(C) is substituted 3- to 10-memberedheterocyclyl.

In some embodiments of compounds of Formula I-III, R′ is —H. In someembodiments, R′ is unsubstituted C₁₋₄ alkyl. In some embodiments, R′ iscycloalkyl. In some embodiments, R″ is —H. In some embodiments, R″ isunsubstituted C₁₋₄ alkyl. In some embodiments, R″ is cycloalkyl. In someembodiments, R′ and R″ together with the atoms which they substituteform a substituted or unsubstituted 5-, 6-, or 7-membered ring. In someembodiments, R′″ is —H. In some embodiments, R′″ is unsubstituted C₁₋₄alkyl. In some embodiments, R′″ is cycloalkyl.

In another embodiment, the compounds are selected from compounds 1-5,7-12, and 16-46 in Table 1. In some embodiments, the compounds areselected from compounds 1-5, 7-9, 16-23, 26, 27, 30, 31, 34, 35, 38,40-42, 45, and 46. In some embodiments, the compounds are selected fromcompounds 10, 11, 24, 25, 28, 29, 32, 33, 36, 37, 39, 43, and 44. Insome embodiments, the compound is compound 12. In some embodiments, thecompounds are selected from compounds 7, 11, 19, and 20. In anotherembodiment, the compounds are selected from compounds 6 and 13-15 inTable 1.

Formulations and Routes of Administration

The compounds described herein, or pharmaceutically acceptable additionsalts or hydrates thereof, can be delivered to a patient using a widevariety of routes or modes of administration. Suitable routes ofadministration include, but are not limited to, inhalation, transdermal,oral, rectal, transmucosal, intestinal and parenteral administration,including intramuscular, subcutaneous and intravenous injections.

The compounds described herein, or pharmaceutically acceptable saltsand/or hydrates thereof, may be administered singly, in combination withother compounds of the invention, and/or in cocktails combined withother therapeutic agents. Of course, the choice of therapeutic agentsthat can be co-administered with the compounds of the invention willdepend, in part, on the condition being treated.

For example, when administered to a patient undergoing cancer treatment,the compounds may be administered in cocktails containing otheranti-cancer agents and/or supplementary potentiating agents. Thecompounds may also be administered in cocktails containing agents thattreat the side-effects of radiation therapy, such as anti-emetics,radiation protectants, etc.

Anti-cancer drugs that can be co-administered with the compoundsdisclosed herein, but are not limited to Aminoglutethimide;Asparaginase; Bleomycin; Busulfan; Carboplatin; Carmustine (BCNU);Chlorambucil; Cisplatin (c/s-DDP); Cyclophosphamide; Cytarabine HCl;Dacarbazine; Dactinomycin; Daunorubicin HCl; Doxorubicin HCl;Estramustine phosphate sodium; Etoposide (VP-16); Floxuridine;Fluorouracil (5-FU); Flutamide; Hydroxyurea (hydroxycarbamide);Ifosfamide; Interferon α-2a, α-2b, Lueprolide acetate (LHRH-releasingfactor analogue); Lomustine (CCNU); Mechlorethamine HCl (nitrogenmustard); Melphalan; Mercaptopurine; Mesna; Methotrexate (MTX);Mitomycin; Mitotane (o.p′-DDD); Mitoxantrone HCl; Octreotide;Plicamycin; Procarbazine HCl; Streptozocin; Tamoxifen citrate;Thioguanine; Thiotepa; Vinblastine sulfate; Vincristine sulfate;Amsacrine (m-AMSA); Azacitidine; Hexamethylmelamine (HMM); Interleukin2; Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone; MGBG);Pentostatin; Semustine (methyl-CCNU); Teniposide (VM-26); paclitaxel andother taxanes; and Vindesine sulfate.

Supplementary potentiating agents that can be co-administered with thecompounds of the invention include, but are not limited to, tricyclicanti-depressant drugs (such as imipramine, desipramine, amitriptyline,clomipramine, trimipramine, doxepin, nortriptyline, protriptyline,amoxapine and maprotiline); non-tricyclic and anti-depressant drugs(such as sertraline, trazodone and citalopram); Ca²⁺ antagonists (suchas verapamil, nifedipine, nitrendipine and caroverine); Amphotericin(such as Tween 80 and perhexiline maleate); triparanol analogues (suchas tamoxifen); antiarrhythmic drugs (such as quinidine);antihypertensive drugs (such as reserpine); thiol depleters (such asbuthionine and sulfoximine); and calcium leucovorin.

The active compound(s) may be administered per se or in the form of apharmaceutical composition wherein the active compound(s) is inadmixture with one or more pharmaceutically acceptable carriers,excipients or diluents. Pharmaceutical compositions for use with thecompounds described above may be formulated in conventional manner usingone or more physiologically acceptable carriers comprising excipientsand auxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee (tablet) cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant (such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In the case of a pressurized aerosol the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of gelatin for use in an inhaler or insufflatormay be formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection (such as by bolus injection or continuous infusion).Formulations for injection may be presented in unit dosage form (inampoules or in multi-dose containers) with an added preservative. Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions.

Suitable lipophilic solvents or vehicles include fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension (such assodium carboxymethyl cellulose, sorbitol, or dextran). Optionally, thesuspension may also contain suitable stabilizers or agents whichincrease the solubility of the compounds to allow for the preparation ofhighly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle (such as sterile pyrogen-freewater) before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas (such as containing conventionalsuppository bases like cocoa butter or other glycerides).

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (such assubcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, the compounds may be formulated with suitablepolymeric or hydrophobic materials (such as an emulsion in an acceptableoil) or ion exchange resins, or as sparingly soluble derivatives (suchas a sparingly soluble salt).

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Effective Dosages

Pharmaceutical compositions suitable for use with the compoundsdescribed above include compositions wherein the active ingredient iscontained in a therapeutically effective amount (an amount effective toachieve its intended purpose).

Of course, the actual amount effective for a particular application willdepend on the condition being treated. For example, when administered inmethods to inhibit cell proliferation, such compositions will contain anamount of active ingredient effective to achieve this result. Whenadministered to patients suffering from disorders characterized byabnormal cell proliferation, such compositions will contain an amount ofactive ingredient effective to prevent the development of or alleviatethe existing symptoms of, or prolong the survival of, the patient beingtreated. For use in the treatment of cancer, a therapeutically effectiveamount further includes that amount of compound which arrests orregresses the growth of a tumor. Determination of an effective amount iswell within the capabilities of those skilled in the art.

For any compound described herein the therapeutically effective amountcan be initially determined from cell culture arrays. Target plasmaconcentrations will be those concentrations of active compound(s) thatare capable of inducing at least about 25% inhibition of cellproliferation in cell culture assays, depending, of course, on theparticular desired application. Target plasma concentrations of activecompound(s) that are capable of inducing at least about 50%, 75%, oreven 90% or higher inhibition of cell proliferation in cell cultureassays are preferred. The percentage of inhibition of cell proliferationin the patient can be monitored to assess the appropriateness of theplasma drug concentration achieved, and the dosage can be adjustedupwards or downwards to achieve the desired percentage of inhibition.

Therapeutically effective amounts for use in humans can also bedetermined from animal models. For example, a dose for humans can beformulated to achieve a circulating concentration that has been found tobe effective in animals. Useful animal models for diseases characterizedby abnormal cell proliferation are well-known in the art. In particular,the following references provide suitable animal models for cancerxenografts (Corbett et al., 1996, J. Exp. Ther. Oncol. 1:95-108; Dykeset al., 1992, Contrib. Oncol. Basel. Karger 42:1-22), restenosis (Carteret al., 1994, J. Am. Coll. Cardiol: 24(5): 1398-1405), atherosclerosis(Zhu et al., 1994, Cardiology 85(6):370-377) and neovascularization(Epstein et al., 1987, Cornea 6(4):250-257). The dosage in humans can beadjusted by monitoring inhibition of cell proliferation and adjustingthe dosage upwards or downwards, as described above.

A therapeutically effective dose can also be determined from human datafor compounds which are known to exhibit similar pharmacologicalactivities. Adjusting the dose to achieve maximal efficacy in humansbased on the methods described above and other methods as are well-knownin the art is well within the capabilities of the ordinarily skilledartisan.

In the case of local administration, the systemic circulatingconcentration of administered compound will not be of particularimportance. In such instances, the compound is administered so as toachieve a concentration at the local area effective to achieve theintended result.

When treating disorders characterized by abnormal cell proliferation,including cancer, a circulating concentration of administered compoundof about 0.001 μM to about 20 μM is considered to be effective, or about0.1 μM to about 5 μM.

Patient doses for oral administration of the compounds described hereinfor the treatment or prevention of cell proliferative disorderstypically range from about 80 mg/day to 16,000 mg/day, more typicallyfrom about 800 mg/day to 8000 mg/day, and most typically from about 800mg/day to 4000 mg/day. Stated in terms of patient body weight, typicaldosages range from about 1 to 200 mg/kg/day, more typically from about10 to 100 mg/kg/day, and most typically from about 10 to 50 mg/kg/day.Stated in terms of patient body surface areas, typical dosages rangefrom about 40 to 8000 mg/m²/day, more typically from about 400 to 4000mg/m²/day, and most typically from about 400 to 2000 mg/m²/day.

For other modes of administration, dosage amount and interval can beadjusted individually to provide plasma levels of the administeredcompound effective for the particular clinical indication being treated.For use in the treatment of tumorigenic cancers, the compounds can beadministered before, during or after surgical removal of the tumor. Forexample, the compounds can be administered to the tumor via injectioninto the tumor mass prior to surgery in a single or several doses. Thetumor, or as much as possible of the tumor, may then be removedsurgically. Further dosages of the drug at the tumor site can be appliedpost removal. Alternatively, surgical removal of as much as possible ofthe tumor can precede administration of the compounds at the tumor site.

Combined with the teachings provided herein, by choosing among thevarious active compounds and weighing factors such as potency, relativebioavailability, patient body weight, severity of adverse side-effectsand preferred mode of administration, an effective prophylactic ortherapeutic treatment regimen can be planned which does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. Of course, many factorsare important in determining a therapeutic regimen suitable for aparticular indication or patient. Severe indications such as invasive ormetastasized cancer may warrant administration of higher dosages ascompared with less severe indications such early-detected,non-metastasized cancer.

EXAMPLES

Compounds of Formulas I-III are listed and identified with ¹H-NMR datain Table I. ND indicates that ¹H-NMR data was not identified. Thecompounds listed in Table I are further characterized in Table II.Methods for preparing each of the compounds in Table I are alsoidentified in Table II. NA in the monomer synthesis column of Table IIindicates that the monomer used as the starting material wascommercially available except for compounds 51, 52, 53, 54, 55, 56, 58,60, 65 and 68. Methods for the preparation of compounds 51, 52, 53, 54,55, 56, 58, 60, 65 and 68 are described elsewhere in the Examples.

Methanesulfonyl chloride (1.5 eq.) was added to a stirred solution ofN-methylimidazole (1.0 eq.) in dichloromethane (25 mL), cooled to 0° C.and the reaction mixture was stirred for 10 to 15 min. Carboxylic acid A(1.0 eq.) was added at 0° C. and again the reaction mixture was stirredfor 20 min at 10° C. to 15° C. Amine B (1.2 eq.) was added to thereaction mixture, which was subsequently heated in a sealed glass tubeat 55° C. to 60° C. for 16 h. After completion of the reaction,volatiles were removed under reduced pressure. The residual material wastriturated with dichloromethane (50 mL), filtered and the wet cake waswashed with dichloromethane (100 mL) then dried under reduced pressureto obtain pure product. Additional purification by flash chromatographyover silica was performed when necessary.

HATU (1.5 eq.) was added to a stirred solution of Carboxylic acid A (1.0eq.) and Amine B (1.2 eq.) in DMF (25 mL) at 0° C. and, after 30 min. ofadditional stirring, DIPEA (4.0 eq.) was added in dropwise fashion andthe total reaction mixture was stirred at RT for 16 h. After completionof the reaction, ice water was added to the reaction mixture and theprecipitated solid was filtered and washed with ethyl acetate (100 ml)and diethyl ether (100 ml) before drying under reduced pressure toobtain pure product. Additional purification by flash chromatographyover silica was performed when necessary.

1-Propanephosphonic acid cyclic anhydride (1.5 eq.) and DIPEA (4 eq.)were added to a stirred solution of Carboxylic acid A (1.0 eq.) andAmine B (1.2 eq.) in DMF (25 mL) at RT. The reaction mixture was stirredfor 16 h at RT. The reaction mixture was then poured into ice water,stirred for 5 min. and the resulting precipitate was filtered and washedwith water. The wet cake was dried under reduced pressure and washedwith diethyl ether and n-pentane to obtain a crude product. Additionalpurification by flash chromatography over silica was performed whennecessary.

COMU (1.5 eq.) and DIPEA (4 eq.) were added to a stirred solution ofCarboxylic acid A (1.0 eq.) and Amine B (1.2 eq.) in THF (2 mL) at RT.The reaction mixture was stirred for 16 h at RT. The reaction mixturewas then poured in ice water, stirred for 5 min. and the resultingprecipitate was filtered and washed with water. The cake was dried underreduced pressure and washed with diethyl ether and n-pentane to obtain acrude product. Additional purification by flash chromatography oversilica was performed when necessary.

POCl₃ (3 eq.) was added to a stirred solution of carboxylic acid A (1.0eq.) and amine B (1.0 eq.) in pyridine (25 mL) at 0° C. The reactionmixture was stirred for 1 h at RT. The reaction mixture was thenfiltered and the filtrate was diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain the crudeproduct, which was then purified by preparative HPLC.

1-Bromo-3-cyclopropylbenzene (0.20 g, 1.4 mmol, 1.0 eq.),6-Aminopyridine-3-boronic acid (0.28 g, 1.4 mmol, 1.0 eq.) and CS₂CO₃(1.41 g, 4.3 mmol, 1.5 eq.) were added to a mixture of dioxane (8 mL)and water (2 mL) which was subsequently degassed with argon for 30 min.Pd(PPh₃)₄ (0.087 g, 4.3 mmol, 0.05 eq.) was added and the reactionmixture was heated to 90° C. for 16 h. After completion of the reaction,the reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The resulting crude material was dissolved inethyl acetate (100 mL) and washed with cold water (100 mL) and brine (25mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 25%ethyl acetate in petroleum ether to obtain pure5-(3-cyclopropylphenyl)pyridin-2-amine (80 mg; 37%).

Step-1: CS₂CO₃ (56.6 g, 174.4 mmol, 3.0 eq.) and NaI (872 mg, 5.81 mmol,0.1 eq.) were added to a stirred solution of 3-bromophenol (10 g, 58.13mmol, 1.0 eq.) and bromocyclopropane (13.95 g, 116.2 mmol, 2.0 eq.) inDMF (50 mL). The reaction mixture was heated to 150° C. for 16 h afterwhich time it was allowed to cool to RT. The reaction mixture was thendiluted with ethyl acetate (200 mL) then washed with chilled water (100mL) and brine (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over silica gel 100-200mesh) eluting with 2% ethyl acetate in petroleum ether to obtain pure1-bromo-3-(cyclopropyloxy)benzene (4.0 g; 32.5%).

Step-2: A stirred solution of 1-bromo-3-(cyclopropyloxy)benzene (1 g,4.71 mmol, 1.0 eq.), 6-aminopyridin-3-ylboronic acid (0.65 g, 4.712mmol, 1.0 eq.), and CS₂CO₃ (4.6 g, 14.13 mmol, 3.0 eq.) in a mixture ofdioxane (30 mL) and water (10 mL) was degassed with argon for 30 min.Pd(PPh₃)₄ (0.272 g, 0.235 mmol, 0.05 eq.) was added and the reactionmixture was heated to 90° C. for 16 h after which time it was allowed tocool to RT. The reaction mixture was then then filtered and the filtratewas concentrated under reduced pressure. The resulting crude materialwas diluted with ethyl acetate (200 mL) then washed with chilled water(100 mL) and brine (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over silica gel 100-200mesh) eluting with 25% Ethyl acetate in petroleum ether to obtain pure5-[3-(cyclopropyloxy)phenyl]pyridin-2-amine (1.0 g; 56.6%).

Step-1: BINAP (0.079 g, 0.11 mmol, 0.01 eq.), Pd₂(dba)₃ (100 mg, 0.11mmol, 0.01 eq.), DBU (1.73 g, 10.28 mmol, 0.8 eq.) and Sodium t-butoxide(1.8 g, 19.06 mmol, 1.5 eq.) were added to a stirred solution of1,3-dibromobenzene (3 g, 12.8 mmol, 1.0 eq.) and cyclopropylamine (0.511g, 8.9 mmol, 0.7 eq.) in toluene (50 mL) under a nitrogen atmosphere.The reaction mixture was heated to 100° C. for 10 h after which time itwas allowed to cool to RT. The reaction mixture was then then filteredand the filtrate was concentrated under reduced pressure. The resultingcrude material was diluted with ethyl acetate (200 mL) then washed withchilled water (100 mL) and brine (50 mL). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct. This material was purified by flash chromatography (usingsilica gel 100-200 mesh) eluting with 25% Ethyl acetate in petroleumether to obtain pure 3-bromo-N-cyclopropylaniline (0.5 g; 18.5%).

Step-2: A stirred solution of 3-bromo-N-cyclopropylaniline (1 g, 4.73mmol, 1.0 eq.), 6-aminopyridin-3-ylboronic acid (0.65 g, 4.73 mmol, 1.0eq.), and CS₂CO₃ (4.6 g, 14.13 mmol, 3.0 eq.) in a mixture of dioxaneand water (3:1.40 mL) was degassed with argon for 30 min. Pd(PPh₃)₄(0.272 g, 0.235 mmol, 0.05 eq.) was added and the reaction mixture washeated to 90° C. for 16 h after which time it was allowed to cool to RT.The reaction mixture was then then filtered and the filtrate wasconcentrated under reduced pressure. The resulting crude material wasdiluted with ethyl acetate (200 mL) then washed with chilled water (100mL) and brine (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (using silica gel 100-200mesh) eluting with 25% Ethyl acetate in petroleum ether to obtain pure5-[3-(cyclopropylamino)phenyl]pyridin-2-amine (0.6 g; 57%).

Step-1: BINAP (0.266 g, 0.42 mmol, 0.01 eq.), Pd₂(dba)₃ (0.391 g, 0.42mmol, 0.01 eq.), DBU (5.19 g, 34.18 mmol, 0.8 eq.) and Sodium t-butoxide(6.15 g, 64.1 mmol, 1.5 eq.) were added to a stirred solution of1,3-dibromobenzene (10 g, 42.7 mmol, 1.0 eq.), and N-methylpiperazine(2.99 g, 29.9 mmol, 0.7 eq.) in toluene (200 mL) under a nitrogenatmosphere. The reaction mixture was heated to 100° C. for 10 h afterwhich time it was allowed to cool to RT. The reaction mixture was thenfiltered and the filtrate was concentrated under reduced pressure. Theresulting crude material was diluted with ethyl acetate (200 mL) thenwashed with chilled water (100 mL) and brine (50 mL). The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude product. This material was purified by flash chromatography (oversilica gel 100-200 mesh) eluting with 25% Ethyl acetate in petroleumether to obtain pure 1-(3-bromophenyl)-4-methylpiperazine (4.0 g; 37%).

Step-2: A stirred solution of 1-(3-bromophenyl)-4-methylpiperazine (1.7g, 6.69 mmol, 1.0 eq.), 6-aminopyridin-3-ylboronic acid (0.923 g, 6.69mmol, 1.0 eq.) and Na₂CO₃ (1.4 g, 13.38 mmol, 2.0 eq.) in a mixture oftoluene, EtOH and water (2:2:1.25 mL) was degassed with argon for 30min. Pd(PPh₃)₄ (0.386 g, 0.334 mmol, 0.05 eq.) was added and thereaction mixture was heated to 90° C. for 16 h after which time it wasallowed to cool to RT. The reaction mixture was then filtered and thefiltrate was concentrated under reduced pressure. The resulting crudematerial was diluted with ethyl acetate (200 mL) then washed withchilled water (100 mL) and brine (50 mL). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct. This material was purified by flash chromatography (over silicagel 100-200 mesh) eluting with 25% Ethyl acetate in petroleum ether toobtain pure 5-[3-(4-methylpiperazin-1-yl)phenyl]pyridin-2-amine (1.0 g;55.8%).

Step-1: 3-Bromophenol (5.0 g, 29.06 mmol) and 2-(morpholin-4-yl)ethanol(4.18 g, 29.06 mmol) were added to a stirred solution of TPP (8.3 g,31.97 mmol, 1.0 eq.) in THF (100 mL) at RT. The reaction mixture wascooled to 0° C. and DIAD (6.45 g, 31.97 mmol) was added. The reactionmixture was stirred at RT for 16 h then quenched with ice water andextracted with ethyl acetate (3×25 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to give crudeproduct. This material was purified by flash chromatography (over silicagel 100-200 mesh) eluting with 75% Ethyl acetate in petroleum ether toobtain pure 4-[2-(3-bromophenoxy)ethyl]morpholine (3.0 g; 34.4%).

Step-2: A stirred solution of 1-[2-(3-bromophenoxy)ethyl]morpholine (1g, 3.35 mmol, 1.0 eq.), 6-aminopyridin-3-ylboronic acid (0.463 g, 3.35mmol, 1.0 eq.), and CS₂CO₃ (3.26 g, 1.05 mmol, 3.0 eq.) in a mixture ofdioxane (30 mL) and water (10 mL) was degassed with argon for 30 min.Pd(PPh₃)₄ (0.193 g, 0.167 mmol, 0.05 eq.) was added and the reactionmixture was heated to 90° C. for 16 h after which time it was allowed tocool to RT. The reaction mixture was then filtered and the filtrate wasconcentrated under reduced pressure. The resulting crude material wasdiluted with ethyl acetate (200 mL) then washed with chilled water (100mL) and brine (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over silica gel 100-200mesh) eluting with 25% ethyl acetate in petroleum ether to obtain pure5-[3-(4-methylpiperazin-1-yl)phenyl]pyridin-2-amine (300 mg; 28.8%).

A solution of 3-bromobiphenyl (500 mg, 2.155 mmol, 1.0 eq.),6-aminopyridin-3-ylboronic acid (0.297 g, 2.15 mmol, 1.0 eq.), andNa₂C₀₃ (452 mg, 4.31 mmol, 2.0 eq.) in a mixture of toluene, EtOH andwater (2:2:1, 5 mL) was degassed with argon for 30 min. Pd(PPh₃)₄ (0.124g, 0.107 mmol, 0.05 eq.) was added and the reaction mixture was heatedto 90° C. for 16 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The resulting crude material was diluted withethyl acetate (200 mL) then washed with chilled water (100 mL) and brine(50 mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 25%Ethyl acetate in petroleum ether to obtain pure5-(biphenyl-3-yl)pyridin-2-amine (200 mg; 37.7%).

A solution of phenylboronic acid (500 mg, 4.09 mmol, 1.0 eq.),5-bromopyrimidin-2-amine (0.709 g, 4.09 mmol, 1.0 eq.), and Na₂C₀₃ (860mg, 8.19 mmol, 2.0 eq.) in a mixture of toluene, EtOH and water (2:2:1.5mL) was degassed with argon for 30 min. Pd(PPh₃)₄ (0.236 g, 0.204 mmol,0.05 eq.) was added and the reaction mixture was heated to 90° C. for 16h after which time it was allowed to cool to RT. The reaction mixturewas then filtered and the filtrate was concentrated under reducedpressure. The resulting crude material was diluted with ethyl acetate(200 mL) then washed with chilled water (100 mL) and brine (50 mL). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude product. This material was purified by flashchromatography (over silica gel 100-200 mesh) eluting with 25% Ethylacetate in petroleum ether to obtain pure 5-phenylpyrimidin-2-amine (200mg; 28.5%).

A solution of 3-(3-bromophenyl)oxetane (1 g, 4.71 mmol, 1.0 eq.),6-aminopyridin-3-ylboronic acid (0.658 g, 4.71 mmol, 1.0 eq.), andCS₂CO₃ (4.6 g, 14.13 mmol, 3.0 eq.) in a mixture of dioxane (10 mL) andwater (3 mL) was degassed with argon for 30 min. Pd(PPh₃)₄ (0.272 g,0.235 mmol, 0.05 eq.) was added and the reaction mixture was heated to90° C. for 16 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The resulting crude material was diluted withethyl acetate (200 mL) then washed with chilled water (100 mL) and brine(50 mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 25%Ethyl acetate in petroleum ether to obtain pure5-[3-(oxetan-3-yl)phenyl]pyridin-2-amine (600 mg; 56.2%).

A solution of 1-bromo-3-cyclobutylbenzene (500 mg, 2.38 mmol, 1.0 eq.),6-aminopyridin-3-ylboronic acid (0.328 g, 2.38 mmol, 1.0 eq.), andCS₂CO₃ (2.32 g, 7.14 mmol, 3.0 eq.) in a mixture of dioxane (5 mL) andwater (3 mL) was degassed with argon for 30 min. Pd(PPh₃)₄ (0.137 g,0.119 mmol, 0.05 eq.) was added and the reaction mixture was heated to90° C. for 16 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The resulting crude material was diluted withethyl acetate (200 mL) then washed with chilled water (100 mL) and brine(50 mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 25%Ethyl acetate in petroleum ether to obtain pure5-(3-cyclobutylphenyl)pyridin-2-amine (300 mg; 56.2%).

A stirred solution of 1-bromo-3-tert-butylbenzene (500 mg, 2.35 mmol,1.0 eq.), 6-aminopyridin-3-ylboronic acid (0.325 g, 2.35 mmol, 1.0 eq.),and CS₂CO₃ (2.29 g, 7.05 mmol, 3.0 eq.) in a mixture of dioxane (5 mL)and water (3 mL) was degassed with argon for 30 min. Pd(PPh₃)₄ (0.136 g,0.117 mmol, 0.05 eq.) was added and the reaction mixture was heated to90° C. for 16 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The resulting crude material was diluted withethyl acetate (200 mL) then washed with chilled water (100 mL) and brine(50 mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 25%Ethyl acetate in petroleum ether to obtain5-(3-tert-butylphenyl)pyridin-2-amine (250 mg; 46.9%).

A stirred solution of 5-bromopyridin-2-amine (77 mg, 0.45 mmol, 1.0eq.), 5-chloro-2-methoxyphenylboronic acid (100 mg, 0.54 mmol, 1.2 eq.),and K₃PO₄ (114 mg, 0.54 mmol, 1.2 eq.) in a mixture of toluene (20 mL)and water (10 mL) was degassed with argon for 30 min. Pd (PPh₃)₄ (10.4mg 0.009 mmol 0.02 eq.) was added and the reaction mixture was heated to80° C. for 8 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The resulting material was diluted with ethylacetate (10 mL), then washed with chilled water (10 mL) and brine (10mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 20-25%ethyl acetate in petroleum ether to obtain5-(5-chloro-2-methoxyphenyl)pyridin-2-amine (80 mg; 59.7%).

A stirred solution of 5-bromopyridin-2-amine (77 mg, 0.45 mmol, 1.0eq.), 5-Chloro-4-methoxyphenylboronic acid (100 mg, 0.54 mmol, 1.2 eq.),and K₃PO₄ (114 mg, 0.54 mmol, 1.2 eq.) in Toluene:water (20:10 mL) wasdegassed with argon for 30 min. Pd (PPh₃)₄ (10.4 mg 0.009 mmol, 0.02eq.) was added and the reaction mixture was heated to 80° C. for 8 hafter which time it was allowed to cool to RT. The reaction mixture wasfiltered and filtrate was concentrated under reduced pressure. Theremaining material was diluted with ethyl acetate (10 mL), then washedwith chilled water (10 mL) and brine (10 mL). The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude product. This material was purified by flash chromatography (oversilica gel 100-200 mesh) by eluting with 20-25% ethyl acetate inpetroleum ether to obtain 5-(5-chloro-4-methoxyphenyl)pyridin-2-amine(90 mg, 67.1%).

Step 1: BINAP (0.414 g, 0.667 mmol, 0.009 eq.), Pd₂(dba)₃ (0.300 g,0.222 mmol, 0.003 eq.), DBU (9.7 g, 59.99 mmol, 0.81 eq.) and sodiumt-butoxide (10.6 g, 111.1 mmol, 1.5 eq.) were added to a stirredsolution of 1,3-dibromo-5-chlorobenzene (20 g, 74.1 mmol, 1.0 eq.), andN-methylpiperazine (6.7 g, 66.7 mmol, 0.9 eq.) in toluene (200 mL) undera nitrogen atmosphere. The reaction mixture was heated to 100° C. for 48h after which time it was allowed to cool to RT. The reaction mixturewas then filtered and the filtrate was concentrated under reducedpressure. The resulting crude material was diluted with ethyl acetate(200 mL) then washed with chilled water (100 mL) and brine (50 mL). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude product. This material was purified by flashchromatography over neutral alumina eluting with 25% ethyl acetate inpetroleum ether to obtain pure1-(3-bromo-5-chlorophenyl)-4-methylpiperazine (9.0 g; 42%).

Step 2: Pd(PPh₃)₄ (0.802 g, 0.694 mmol, 0.1 eq.) and Cs₂CO₃ (3.3 g,10.42 mmol, 1.5 eq) were added to a stirred solution of1-(3-bromo-5-chlorophenyl)-4-methylpiperazine (2 g, 6.94 mmol, 1.0 eq.)and 6-aminopyridine-3-bornic acid (0.862 g, 0.694 mmol, 0.9 eq.) indioxane (20 ml, previously degassed with nitrogen for 10 min). Thereaction mixture was heated at 100° C. for 18 h after which time it wasallowed to cool to RT. The reaction mixture was then filtered and thefiltrate was diluted with ethyl acetate (100 mL) and washed with waterand brine (100 mL each). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over silica gel 100-200mesh) eluting with 10% methanol in DCM to afford pure5-[5-chloro-3-(4-methylpiperazin-1-yl)phenyl]pyridin-2-amine (1.2 g;57%).

Pd(PPh₃)₄ (0.50 g, 0.454 mmol, 0.1 eq.) and CS₂CO₃ (2.95 g, 9.08 mmol,2.0 eq) were added to a stirred solution of1-(3-bromo-5-chlorophenyl)-4-methylpiperazine (1.30 g, 4.54 mmol, 1.0eq.) and 6-amino-2-methylpyridine-3-boronic acid (1.00 g g, 4.54 mmol,1.0 eq.) in dioxane (20 mL, previously degassed with nitrogen for 10min). The reaction mixture was heated at 80° C. for 18 h after whichtime it was allowed to cool to RT. The reaction mixture was thenfiltered and the filtrate was diluted with ethyl acetate (100 mL) andwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct. This material was purified by flash chromatography (over silicagel 100-200 mesh) eluting with 10% methanol in DCM to afford pure5-[5-chloro-3-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-amine(1.2 g; 85%).

Step 1: m-CPBA (12.5 g, 73.05 mmol, 4.0 eq.) was added to a stirredsolution of cyclopropyl 3,5-dichlorophenyl sulphide (4.0 g, 18.26 mmol,1.0 eq.) in DCM (40 mL) at 0° C. The resulting reaction mixture wasstirred for 2 h at RT then diluted with ethyl acetate (100 mL) andwashed with a 1N NaOH (100 mL) aqueous solution. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to give crudecyclopropyl 3,5-dichlorophenyl sulfone (5 g) [m/z (M+H⁺)=251.00],

Step 2: BINAP (33 mg, 0.053 mmol, 0.009 eq.), Pd₂(dba)₃ (16 mg, 0.017mmol, 0.003 eq.), DBU (784 mg, 4.840 mmol, 0.81 eq.) and sodiumt-butoxide (860 mg, 8.964 mmol, 1.50 eq.) were added to a stirredsolution of cyclopropyl 3,5-dichlorophenyl sulphone (1500 mg, 5.976mmol, 1.00 eq.), and N-methylpiperazine (597 mg, 5.976 mmol, 1.00 eq.)in dioxane (20 mL) under a nitrogen atmosphere. The reaction mixture washeated to 100° C. for 16 h after which time it was allowed to cool toRT. The reaction mixture was then filtered and the filtrate was dilutedwith ethyl acetate (100 mL) then washed with water and brine (100 mLeach). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product. This material was purified byflash chromatography (over neutral alumina) eluting with 100% ethylacetate to obtain pure1-[3-chloro-5-(cyclopropylsulfonyl)phenyl]-4-methylpiperazine (1.3 g;69%) [m/z (M+H⁺)=315.18],

Step 3: Pd(PPh₃)₄ (92 mg, 0.079 mmol, 0.05 eq.) and CS₂CO₃ (1554 mg 4.78mmol, 3.0 eq.) were added to a stirred solution of1-[3-chloro-5-(cyclopropylsulfonyl)phenyl]-4-methylpiperazine (500 mg,1.59 mmol, 1.0 eq.) and 6-aminopyridine-3-boronic acid (220 mg, 1.59mmol, 1.0 eq.) in dioxane (5 ml). The reaction mixture was heated at100° C. for 18 h after which time it was allowed to cool to RT. Thereaction mixture was then filtered and the filtrate was diluted withethyl acetate (100 mL) then washed with water and brine (100 mL each).The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to give crude product. This material was purified by flashchromatography (over silica gel 100-200 mesh) eluting with 10% methanolin DCM to afford pure5-[3-(cyclopropylsulfonyl)-5-(4-methylpiperazin-1-yl)phenyl]pyridin-2-amine(0.25 g; 42%).

Pd(PPh₃)₄ (80 mg, 0.075 mmol, 0.1 eq.) and CS₂CO₃ (500 mg, 1.50 mmol,2.0 eq.) were added to a stirred solution of1-[3-chloro-5-(cyclopropylsulfonyl)phenyl]-4-methylpiperazine (230 mg,0.75 mmol, 1.0 eq.) and6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(200 mg, 0.90 mmol, 1.2 eq.) in dioxane (5 ml). The reaction mixture washeated at 100° C. for 18 h after which time it was allowed to cool toRT. The reaction mixture was then filtered and the filtrate was dilutedwith ethyl acetate (100 mL) then washed with water and brine (100 mLeach). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give crude product. This material was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 10%methanol in DCM to afford pure5-[3-(cyclopropylsulfonyl)-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-amine(160 mg; 57%) [m/z (M+H⁺)=387.29].

Pd₂(dba)₃ (72 mg, 0.078 mmol, 0.01 eq.) and K₃PO₄ (3.32 g, 15.63 mmol,2.0 eq.) were added to a solution of thiophene-3-boronic acid (1.00 g,7.815 mmol, 1.0 eq.) and 5-bromopyridin-2-amine (1.76 g, 10.159 mmol,1.3 eq.) in n-butanol (100 mL) under an argon atmosphere. The reactionmixture was heated to 90° C. for 16 h after which time it was allowed tocool to RT. The reaction mixture was then diluted with ethyl acetate(100 mL) then washed with water and brine (100 mL each). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude product. This material was purified by flash chromatography(over neutral alumina) eluting with 100% ethyl acetate to obtain pure5-(thiophen-3-yl)pyridin-2-amine (200 mg; 15%).

Pd(PPh₃)₄ (651 mg, 0.564 mmol, 0.1 eq.) and Cs₂CO₃ (5.50 g, 16.92 mmol,3.0 eq.) were added to a stirred solution of 4-bromo-2-methylthiophene(1.00 g, 5.64 mmol, 1.0 eq.) and 6-aminopyridin-3-ylboronic acid (1.10g, 8.47 mmol, 1.5 eq.) in a mixture of dioxane (10 ml) and water (3 ml)at RT under a nitrogen atmosphere. The reaction mixture was heated to90° C. for 16 h after which time it was allowed to cool to RT. Thereaction mixture was then diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct. This material was purified by flash chromatography (overneutral alumina) eluting with 100% ethyl acetate to obtain pure5-(5-methylthiophen-3-yl)pyridin-2-amine (1.0 g; 46.7%).

Step 1: NaHMDS (2M in THF, 361 mL, 722.5 mmol, 2.5 eq.) was added to astirred solution of 5-bromopyridin-2-amine (50 g, 289.0 mmol, 1.0 eq.)in THF (50 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30min. followed by the addition of (BOC)₂O (82 mL, 375.7 mmol, 1.3 eq.)dissolved in THF (50 mL). The reaction mixture was stirred at RT for 16h then quenched with ice water and extracted with ethyl acetate. Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude product which was purified bytrituration with petroleum ether to obtain pure tert-butyl(5-bromopyridin-2-yl)carbamate (60 g; 76%).

Step 2: Potassium acetate (21.50 g, 219.70 mmol, 3.0 eq.) andPdCl₂(dppf).CH₂Cl₂ (2.99 g, 3.67 mmol, 0.05 eq.) were added to a stirredsolution of (5-bromopyridin-2-yl)carbamate (20.00 g, 73.26 mmol, 1.0eq.) and bis(pinacolato) diboron (37.00 g, 146.50 mmol, 2.0 eq.) indioxane (200 mL) under a nitrogen atmosphere at RT. The reaction mixturewas heated to 100° C. for 16 h after which time it was allowed to coolto RT. The reaction mixture was then filtered and diluted with ethylacetate (100 mL) then washed with water and brine (100 mL each). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude product. This material was purified by flashchromatography (over neutral alumina) eluting with 50% ethyl acetate inpetroleum ether to obtain puretert-butyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(15.0 g; 64%).

Step-3: Bromocyclopropane (13 g, 105.82 mmol, 2.0 eq.), CS₂CO₃ (51 g,158.73 mmol, 3.0 eq.) and NaI (793 mg, 5.29 mmol, 0.1 eq.) were added toa stirred solution of 3-bromobenzenethiol (10 g, 52.91 mmol, 1.0 eq.) inDMF (100 mL) at RT. The reaction mixture was heated to 120° C. for 16 hafter which time it was allowed to cool to RT. The reaction mixture wasthen washed with chilled water and brine (100 mL each). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude product. This material was purified by flash chromatography(over silica gel 100-200 mesh) eluting with 100% petroleum ether toobtain pure 1-bromo-3-(cyclopropylsulfanyl)benzene (7.0 g; 57.7%).

Step 4: m-CPBA (21 g, 122.80 mmol, 4.0 eq.) was added to a stirredsolution of 1-bromo-3-(cyclopropylsulfanyl)benzene (7 g, 30.70 mmol, 1.0eq.) in DCM (200 mL) at 0° C. The reaction mixture was stirred for 16 hat RT. The reaction mixture concentrated under reduced pressure and thendiluted with ethyl acetate (200 mL) and washed with a 1N NaOH aqueoussolution (200 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude1-bromo-3-(cyclopropylsulfonyl)benzene (7.0 g).

Steps 5/6:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(12.3 g, 38.60 mmol, 1.0 eq.), Pd(PPh₃)₄ (4.4 g, 3.86 mmol, 0.1 eq.) andCS₂CO₃ (37.6 g, 115.80 mmol, 3.0 eq.) were added to a stirred solutionof 1-bromo-3-(cyclopropylsulfonyl)benzene (10.0 g, 38.60 mmol, 1.0 eq.)in a mixture of dioxane (200 ml) and water (50 ml) previously degassedwith nitrogen for 10 min. The reaction mixture was heated to 100° C. for18 h after which time it was allowed to cool to RT. The reaction mixturewas filtered and diluted with ethyl acetate (100 mL) then washed withwater and brine (100 mL each). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to obtain crude tert-butyl {5-[3(cyclopropylsulfonyl)phenyl]pyridin-2-yl}carbamate (25.0 g). Thismaterial was dissolved in HCl in dioxane (4N, 50 ml) at 0° C. Thereaction mixture was stirred for 16 h at RT then quenched with ice waterand extracted with ethyl acetate (300 ml). The aqueous layer wasbasified with NaHCO₃ and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine then dried over Na₂SO₄and concentrated under reduced pressure to obtain crude 5-[3(cyclopropylsulfonyl)phenyl]pyridin-2-amine (14 g) which was usedwithout further purification.

6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(150 mg, 0.681 mmol, 1.0 eq.), Pd(pph₃)₄ (78 mg, 0.068 mmol, 0.1 eq.)and CS₂CO₃ (440 mg, 1.362 mmol, 2.0 eq.) were added to a stirredsolution of 1-bromo-3-(cyclopropylsulfonyl)benzene (180 mg, 0.681 mmol,1.0 eq.) in dioxane (5 mL) previously degassed with nitrogen for 10 min.The reaction mixture was heated to 100° C. for 18 h after which time itwas allowed to cool to RT. The reaction mixture was then filtered andthe filtrate was diluted with ethyl acetate (100 mL) then washed withwater and brine (100 mL each). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over neutral alumina)eluting with 10% methanol in DCM to give5-[3-(cyclopropylsulfonyl)phenyl]-6-methylpyridin-2-amine (200 mg; 99%).

Pd(PPh₃)₄ (0.14 g, 0.12 mmol, 0.1 eq.) and Na₂CO₃ (0.53 g, 5.04 mmol,3.6 eq.) were added to a stirred solution of1-bromo-3-(cyclopropyloxy)benzene (0.30 g, 1.40 mmol, 1.0 eq.) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(0.50 g, 2.10 mmol, 1.5 eq.) in a mixture of dioxane (3 mL) and water(1.5 mL) previously degassed with nitrogen for 10 min. The reactionmixture was heated to 100° C. for 16 h after which time it was allowedto cool to RT. The reaction mixture was then filtered and the filtratewas diluted with ethyl acetate (100 mL) then washed with water and brine(100 mL each). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to afford crude product. This material waspurified by flash chromatography (over silica gel 100-200 mesh) elutingwith 40% EtOAc in petroleum ether to afford pure5-[3-(cyclopropyloxy)phenyl]-3-fluoropyridin-2-amine (250 mg; 73.5%)

Pd(PPh₃)₄ (1.1 g, 1.03 mmol, 0.1 eq.) and Na₂CO₃ (1.6 g, 15.37 mmol, 1.5eq.) were added to a stirred solution of 1-bromo-3-cyclopropylbenzene(2.0 g, 10.25 mmol, 1.0 eq.) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(2.6 g, 11.28 mmol, 1.1 eq.) in a mixture of dioxane (3 mL) and water(1.5 mL) previously degassed with argon for 30 min. The reaction mixturewas heated to 80° C. for 2 h after which time it was allowed to cool toRT. The reaction mixture was then filtered through a bed of celite andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (100 mL) then washed with water and brine(100 mL each). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to afford crude product. This material waspurified by flash chromatography (over silica gel 100-200 mesh) elutingwith 100% EtOAc to afford pure5-(3-cyclopropylphenyl)-3-fluoropyridin-2-amine (500 mg; 21.5%)

Pd(PPh₃)₄ (1.40 g, 1.22 mmol, 0.1 eq.) and Na₂CO₃ (1.94 g, 18.39 mmol,1.5 eq.) were added to a stirred solution of 3-bromothiophene (2.00 g,12.26 mmol, 1.0 eq.) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(3.20 g, 13.49 mmol, 1.1 eq.) in a mixture of dioxane (20 mL) and water(5 mL) previously degassed with argon for 30 min. The reaction mixturewas heated to 80° C. for 2 h after which time it was allowed to cool toRT. The reaction mixture was then filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (100 mL) then washed with water and brine (100 mL each). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford crude product. This material was purified by flashchromatography (over silica gel 100-200 mesh) eluting with 100% EtOAc toafford pure 3-fluoro-5-(thiophen-3-yl)pyridin-2-amine (1.3 g; 54.6%).

Pd(PPh₃)₄ (0.89 g, 0.77 mmol, 0.1 eq.) and Na₂CO₃ (1.20 g, 11.58 mmol,1.5 eq.) were added to a stirred solution of1-bromo-3-(cyclopropylsulfonyl)benzene (2.00 g, 7.72 mmol, 1.0 eq.) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(1.80 g, 7.72 mmol, 1.0 eq.) in a mixture of dioxane (20 mL) and water(5 mL) previously degassed with nitrogen for 10 mins. The reactionmixture was heated to 100° C. for 6 h after which time it was allowed tocool to RT. The reaction mixture was then filtered and the filtrate wasdiluted with ethyl acetate (100 mL) then washed with water and brine(100 mL each). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude product. This material waspurified by flash chromatography (over silica gel 100-200 mesh) elutingwith 100% ethyl acetate to yield5-[3-(cyclopropylsulfonyl)phenyl]-3-fluoropyridin-2-amine (600 mg;26.6%)

Synthesis ofN-{5-[3-cycopropylaminol-5-(4-methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(51)

BINAP (14 mg, 0.024 mmol, 0.1 eq.), Pd₂(dba)₃ (21 mg, 0.024 mmol, 0.1eq.), X-Phos (11 mg, 0.024 mmol, 0.1 eq.) and NaOtBu (68 mg, 0.708 mmol,3.0 eq.) were added to a stirred solution ofN-{5-[3-chloro-5-(4-methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(100 mg, 0.236 mmol, 1.0 eq.) and cyclopropylamine (13 mg, 0.236 mmol,1.0 eq.) in dioxane (10 mL) under a nitrogen atmosphere at RT. Thereaction mixture was subsequently heated to 100° C. for 18 h after whichtime it was allowed to cool to RT. The reaction mixture was thenfiltered and the filtrate was diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to give crudeproduct. This material was purified by flash chromatography (over silicagel100-200 mesh) eluting with 10% methanol in DCM to afford pureN-{5-[3-cycopropylaminol-5-(4-methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(20 mg; 19.2%).

Synthesis ofN-{5-[3-cyclopropylamino-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(52)

BINAP (10 mg, 0.017 mmol, 0.05 eq.), Pd₂(dba)₃ (31 mg, 0.034 mmol, 0.1eq.), X-Phos (16 mg, 0.034 mmol, 0.1 eq.) and NaOtBu (49 mg, 0.516 mmol,1.5 eq.) were added to a stirred solution ofN-{5-[3-chloro-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(150 mg, 0.344 mmol, 1.0 eq.) and cyclopropylamine (20 mg, 0.412 mmol,1.2 eq.) in dioxane (10 mL) under a nitrogen atmosphere at RT. Thereaction mixture was subsequently heated to 100° C. for 18 h after whichtime it was allowed to cool to RT. The reaction mixture was thenfiltered and the filtrate was diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to give crudeproduct. This material was purified by flash chromatography (over silicagel 100-200 mesh) eluting with 10% methanol in DCM to afford pureN-{5-[3-cycopropylamino-5-(4-methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(20 mg; 12.7%).

Synthesis ofN-{5-[3-cyclopropyl-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(53)

BINAP (7 mg, 0.012 mmol, 0.05 eq.) Pd₂(dba)₃ (21 mg, 0.024 mmol, 0.1eq.), X-Phos (10 mg, 0.024 mmol, 0.1 eq.) and KF (27 mg, 0.472 mmol, 2.0eq.) were added to a stirred solution ofN-{5-[3-chloro-5-(4-methylpiper-azin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(100 mg, 0.236 mmol, 1.0 eq.) and cyclopropyl boronic acid (24 mg, 0.283mmol, 1.2 eq.) in dioxane (10 mL) under a nitrogen atmosphere at RT. Thereaction mixture was heated at 100° C. for 18 h after which time it wasallowed to cool to RT. The reaction mixture was then filtered and thefiltrate was diluted with ethyl acetate (100 mL) then washed with waterand brine (100 mL each). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give crude product. This materialwas purified by preparative HPLC to afford pureN-{5-[3-cyclopropyl-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(20 mg; 19.8%).

Synthesis ofN-{5-[3-chloro-5-(4-methylpiperazin-1-yl)phenyl]-3-fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide(54)

Step 1: BINAP (2.32 g, 3.70 mmol, 0.1 eq.), Pd(OAc)₂ (0.41 g, 1.86 mmol,0.05 eq.) and Cs₂CO₃ (18.23 g, 55.90 mmol, 1.5 eq.) were added to astirred solution of 1-chloro-3,5-dibromobenzene (10.00 g, 37.00 mmol,1.0 eq.) and6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-fluoropyridin-2-amine(8.97 g, 48.10 mmol, 1.3 eq.) in toluene (200 mL). The reaction mixturewas heated to 100° C. for 16 h after which time it was allowed to coolto RT. The reaction mixture was then filtered, diluted with ethylacetate (100 mL) then washed with water and brine (100 mL each). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude product. This material was purified by flashchromatography (over silica gel 100-200 mesh) eluting with 5% ethylacetate in petroleum ether to afford pure tert-butyl4-[3-chloro-5-(5-fluoro-6-aminopyridin-3-yl)phenyl]piperazine-1-carboxylate(4.10 g; 29.4%)

Step 2: POCl₃ (0.27 mL, 2.94 mmol, 3.0 eq.) was added to a stirredsolution of 2-methylpyrimidine-5-carboxylic acid (136 mg, 0.98 mmol, 1.0eq.) and tert-butyl4-[3-chloro-5-(5-fluoro-6-aminopyridin-3-yl)phenyl]piperazine-1-carboxylate(400 mg, 0.98 mmol, 1.0 eq.) in pyridine (4 ml) at 0° C. The reactionmixture was stirred for 1 h at RT. The reaction mixture was thenfiltered and the filtrate was diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct which was purified by preparative HPLC to give pureN-{5-[3-chloro-5-(4-Boc-piperazin-1-yl)phenyl]-3-fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide(300 mg; 58%).

Step 3:N-{5-[3-chloro-5-(4-Boc-piperazin-1-yl)phenyl]-3-fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide(200 mg, 0.37 mmol) was dissolved in HCl in dioxane (4N, 50 ml) andstirred for 16 h at RT. The solvent was then removed under reducedpressure and the residue was diluted with water, basified with aqeuousNaHCO₃ and extracted with ethyl acetate (300 mL). The organic layer wasseparated, washed with water and brine (100 mL each) then dried overNa₂SO₄ and concentrated under reduced pressure to afford crude product.This material was triturated with hexane to afford pureN-{5-[3-cyclopropyl-5-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide(121 mg; 75%).

Synthesis of2-methyl-N-{5-[3-(pyrrolidin-3-ylamino)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide(55)

Step 1: Pd₂(dba)₂ (1.294 g, 1.413 mmol, 0.1 eq.), Xantphos (0.818 g,1.413 mmol, 0.1 eq.) and CS₂CO₃ (6.890 g, 21.010 mmol, 1.5 eq.) wereadded to a stirred solution of 1-bromo-3-iodobenzene (4.000 g, 14.134mmol, 1.0 eq.) and tert-butyl-3-aminopyrrolidine-1-carboxylate (2.633 g,14.134 mmol, 1.0 eq.) in dioxane (50 mL) under argon atmosphere at RT.The reaction mixture was heated to 100° C. for 16 h after which time itwas allowed to cool to RT. The reaction mixture was then filtered,diluted with ethyl acetate (100 mL) then washed with water and brine(100 mL each). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude product. This material waspurified by flash chromatography (over silica gel 100-200 mesh) elutingwith 30% ethyl acetate in petroleum ether to afford puretert-butyl-3-[(3-bromophenyl)amino]pyrrolidine-1-carboxylate (1.0 g;20.8%).

Step 2: Pd (PPh₃)₄ (169 mg, 0.147 mmol, 0.05 eq.) and CS₂CO₃ (2.867 g,8.823 mmol, 3.0 eq) were added to a stirred solution oftert-butyl-3-[(3-bromophenyl)amino]pyrrolidine-1-carboxylate (1.000 g,2.941 mmol, 1.0 eq.) and 6-aminopyridin-3-ylboronic acid (0.405 g, 2.941mmol, 1.0 eq.) in a mixture of dioxane (30 ml) and water (10 ml) at RTunder a argon atmosphere. The reaction mixture was heated to 100° C. for16 h after which time it was allowed to cool to RT. The reaction mixturewas then filtered and the filtrate was concentrated under reducedpressure. The residue was diluted with ethyl acetate (100 mL) thenwashed with water and brine (100 mL each). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to give crudeproduct. This material was purified by flash chromatography (over silicagel 100-200 mesh) eluting with 40% ethyl acetate in petroleum ether toafford puretert-butyl-3-{[3-(6-aminopyridin-3-yl)phenyl]amino}pyrrolidine-1-carboxylate(300 mg; 29%).

Steps 3/4: 2-Chloro-1-methylpyridinium iodide (288 mg, 11.299 mmol, 2.0eq.) and DIPEA (0.2 mL) were added to a stirred solution oftert-butyl-3-{[3-(6-aminopyridin-3-yl)phenyl]amino}pyrrolidine-1-carboxylate(200 g, 0.565 mmol, 1.0 eq.) and 2-methyl-pyrimidine-5-carboxylic acid(78 mg, 0.565 mmol, 1.0 eq.) in THF (20 mL) at RT. The reaction mixturewas stirred for 48 hours at RT then diluted with ethyl acetate (100 mL)then washed with water and brine (100 mL each). The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude product. This material was purified by preparative HPLC thendissolved in a solution of HCl in dioxane (4N, 50 ml). After stirringfor 1 hour at RT, the reaction mixture was concentrated under reducedpressure and the final product was isolated by trituration with pentaneto give2-methyl-N-{5-[3-(pyrrolidin-3-ylamino)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide(55) (40 mg; 17%).

Synthesis of2-[(2-aminoethyl)amino]-N-[5-(3-cyclopropylphenyl)pyridin-2-yl]pyrimidine-5-carboxamide(56)

Step 1: TEA (1.116 g, 11.049 mmol, 4.0 eq.) and (Boc)₂O (1.204 g, 5.524mmol, 2.0 eq.) were added to a stirred solution of6-[(2-aminoethyl)amino]pyridine-3-carboxylic acid (0.500 g, 2.762 mmol,1.0 eq.) in methanol (5 ml). The reaction mixtures was stirred for 16hours at RT. The reaction mixture was then concentrated under reducedpressure and the residue was dissolved in a mixture of water and aceticacid (50 mL each). After extraction with ethyl acetate (150 mL), thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to give crude product. Trituration with 50% ethylacetate in petroleum ether gave pure6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)pyridine-3-carboxylic acid(200 mg; 25.7%) [m/z (M+H⁺)=282.13],

Steps 2/3: 2-Chloro-1-methylpyridinium iodide (971 mg, 3.809 mmol, 4.0eq.) and DIPEA (0.3 ml, 1.902 mmol, 2.0 eq.) were added to a stirredsolution of 5-(3-cyclopropylphenyl)pyridin-2-amine (200 mg, 0.952 mmol,1.0 eq.) and6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)pyridine-3-carboxylic acid(267 mg, 0.952 mmol, 1.0 eq.) in THF (30 mL). The reaction mixture wasstirred for 16 hours at RT. The reaction mixture was then concentratedunder reduced pressure and the resulting crude product was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 30%ethyl acetate in petroleum ether. The purified material was thendissolved in a solution of HCl in dioxane (4N, 50 ml) and stirred for 1hour at RT. The reaction mixture was then concentrated under reducedpressure to give a residue which was purified by trituration withpentane, resulting in pure2-[(2-aminoethyl)amino]-N-[5-(3-cyclopropylphenyl)pyridin-2-yl]pyrimidine-5-carboxamide(56) (37 mg; 11.1%).

Synthesis of2-[(2-aminoethyl)amino]-N-[5-(3-cyclopropyloxyphenyl)pyridin-2-yl]pyrimidine-5-carboxamide(58) Steps 1/2

Steps 1/2: 2-Chloro-1-methylpyridinium iodide (679 mg, 2.66 mmol, 2.0eq.) and DIPEA (344 mg, 463 μL, 2.66 mmol, 2.0 eq.) were added to astirred solution of 5-[3-(cyclopropyloxy)phenyl]pyridin-2-amine (300 mg,1.33 mmol, 1.0 eq.) and6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)pyridine-3-carboxylic acid(373 mg, 1.33 mmol, 1.0 eq.) in THF (30 mL). The reaction mixture wasstirred for 16 hours at RT. The reaction mixture was then concentratedunder reduced pressure and the resulting crude product was purified byflash chromatography (over silica gel 100-200 mesh) eluting with 30%ethyl acetate in petroleum ether. The purified material was thendissolved in a solution of HCl in dioxane (4N, 50 ml) and stirred for 1hour at RT. The reaction mixture was then concentrated under reducedpressure to give a residue which was purified by trituration withpentane, resulting in2-[(2-aminoethyl)amino]-N-[5-(3-cyclopropyloxyphenyl)pyridin-2-yl]pyrimidine-5-carboxamide(58) (10 mg; 2.8%).

Synthesis ofN-[5-(3-cyclopropylphenyl)pyridin-2-yl]-2-hydroxypyrimidine-5-carboxamide(60)

A mixture ofN-[5-(3-cyclopropylphenyl)pyridin-2-yl]-2-methoxypyrimidine-5-carboxamide(250 mg, 0.722 mmol, 1.0 eq.) and pyridine hydrochloride (332 mg, 2.890mmol, 4.0 eq.) was heated to 150° C. for 6 h after which time it wasallowed to cool to RT. The reaction mixture was then diluted with ethylacetate (100 mL) then washed with water and brine (100 mL each). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to give crude product. This material was purified bypreparative HPLC to giveN-[5-(3-cyclopropylphenyl)pyridin-2-yl]-2-hydroxypyrimidine-5-carboxamide(60) (17 mg; 7.1%).

Synthesis ofN-[5-(3-cyclopropyl-5-hydroxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide(65)

Step 1: POCl₃ (5.30 mL, 56.7 mmol, 3.0 eq.) was added to a stirredsolution of 2-methylpyrimidine-5-carboxylic acid (2.62 g, 18.9 mmol, 1.0eq.) and 5-bromopyridin-2-amine (3.00 g, 18.9 mmol, 1.0 eq.) in pyridine(30 mL) at 0° C. and the resulting solution was stirred for 1 h at RT.The reaction mixture was then filtered and the filtrate was diluted withethyl acetate (100 mL) then washed with water and brine (100 mL each).The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtainN-(5-bromopyridin-2-yl)-2-methylpyrimidine-5-carboxamide (4.00 g;71.9%).

Step 2: Potassium acetate (5.30 g, 54.40 mmol, 4.0 eq.) andPdCl₂(dppf).CH₂Cl₂ (556 mg, 0.68 mmol, 0.05 eq.) were added to a stirredsolution of N-(5-bromopyridin-2-yl)-2-methylpyrimidine-5-carboxamide(4.00 g, 13.60 mmol, 1.0 eq.) and bis(pinacolato)diboron (3.79 g, 14.90mmol, 1.1 eq.) in dioxane (40 mL) under a nitrogen atmosphere at RT. Thereaction mixture was heated to 100° C. for 16 h after which time it wasallowed to cool to RT. The reaction mixture was then filtered, dilutedwith ethyl acetate (100 mL) and washed with water and brine (100 mLeach). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give crude product. This material was purified byflash chromatography (over neutral alumina) eluting with 50% ethylacetate in petroleum ether to obtainN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-2-methylpyrimidine-5-carboxamide(2.00 g; 43%).

Step 3: Pd(PPh₃)₄ (600 mg, 0.53 mmol, 0.1 eq.) and CS₂CO₃ (3.40 g, 10.52mmol, 2.0 eq.) were added to a stirred solution ofN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-2-methylpyrimidine-5-carboxamide(1.78 g, 5.26 mmol, 1.0 eq.) and dibromoanisole (1.40 g, 5.26 mmol, 1.0eq.) in dioxane (14 ml) at RT under a nitrogen atmosphere. The reactionmixture was heated to 100° C. for 16 h after which time it was allowedto cool to RT. The reaction mixture was then filtered and the filtratewas concentrated under reduced pressure. The residue was diluted withethyl acetate (100 mL) and washed with water and brine (100 mL each).The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to give crude product. This material was purified by flashchromatography (over silica gel 230-400 mesh) eluting with 2% methanolin DCM to afford pureN-[5-(3-bromo-5-methoxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide(1.20 g; 57%).

Step 4: Cyclopropylboronic acid (516 mg, 6.0 mmol, 2.0 eq.), Pd₂(dba)₃(274 m g, 0.3 mmol, 0.1 eq.), S-Phos (123 mg, 0.3 mmol, 0.1 eq.) and KF(522 mg, 9.0 mmol, 3.0 eq.) were added to a stirred solution ofN-[5-(3-bromo-5-methoxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide(1200 mg, 3.0 mmol, 1.0 eq.) in dioxane (20 mL). The reaction mixturewas heated to 100° C. for 16 h after which time it was allowed to coolto RT. The reaction mixture was then filtered, diluted with ethylacetate (100 mL) and washed with water and brine (100 mL each). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford crudeN-{5-[3-(cyclopropyloxy)-5-methoxyphenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(600 mg) which was used without further purification.

Step 5: BBr₃ (689 mg, 2.77 mmol, 2.0 eq.) was added drop-wise to astirred solution ofN-{5-[3-(cyclopropyloxy)-5-methoxyphenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide(500 mg, 1.38 mmol, 1.0 eq.) in DCM (5 ml) at −78° C. The reactionmixture was stirred for 2 h at −78° C. then quenched with aqueousNaHCO₃. The reaction mixture was then extracted with ethyl acetate. Theorganic layer was washed with water and brine then dried over Na₂SO₄ andconcentrated under reduced pressure to afford crude product which waspurified by preparative HPLC to giveN-[5-(3-cyclopropyl-5-hydroxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide(65) (35 mg; 7.3%).

Synthesis ofN-{5-[3-(cyclopropylamino)phenyl]-3-fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide(69)

Step 1: BINAP (237 mg, 0.381 mmol, 0.009 eq.), Pd₂(dba)₃, (116 mg, 0.127mmol, 0.003 eq.), DBU (5.5 g, 33.890 mmol, 0.8 eq.) and sodiumtert-butoxide (6.1 g, 63.550 mmol, 1.5 eq.) were added to a stirredsolution of 1,3-dibromobenzene (10.0 g, 42.37 mmol, 1.0 eq.) andcyclopropylamine (2.5 g, 42.37 mmol, 1.0 eq.) in toluene (50 mL) under anitrogen atmosphere. The reaction mixture was heated to 100° C. for 16 hafter which time it was allowed to cool to RT. The reaction mixture wasthen filtered, diluted with ethyl acetate (100 mL) and washed with waterand brine (100 mL each). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting crude material waspurified by flash chromatography (over silica gel 100-200 mesh) elutingwith 10% ethyl acetate in petroleum ether to obtain pure3-bromo-N-cyclopropylaniline (2.0 g; 22.2%).

Step 2: Bis(pinacolato)diboron (1.3 g, 5.209 mmol, 1.10 eq.), potassiumacetate (1.4 g, 14.208 mmol, 3.00 eq.) and Pd(dppf)Cl₂.CH₂Cl₂ (38 mg,0.047 mmol, 0.01 eq.) were added to a stirred solution of3-bromo-N-cyclopropylaniline (1.0 g, 4.736 mmol, 1.00 eq.) in dioxane(200 mL). The reaction mixture was heated to 90° C. for 3 h after whichtime it was allowed to cool to RT. The reaction mixture was thenfiltered, diluted with ethyl acetate (100 mL) and washed with water andbrine (100 mL each). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude product. Thismaterial was purified by flash chromatography (over silica gel 100-200mesh) eluting with 10% ethyl acetate in petroleum ether to obtain pure3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-cyclopropylaniline(1.0 g; 81.4%).

Step 3: POCl₃ (0.4 mL, 4.04 mmol, 3.0 eq.) was added to a stirredsolution of 2-methylpyrimidine-5-carboxylic acid (500 mg, 3.68 mmol, 1.0eq.) and 5-bromo-3-fluoropyridin-2-amine (700 mg, 3.68 mmol, 1.0 eq.) inpyridine (10 ml) at 0° C. The reaction mixture was stirred for 1 h at RTafter which time it was poured into ice water. The resulting solid wasdried to affordN-(5-bromo-3-fluoropyridin-2-yl)-2-methylpyrimidine-5-carboxamide (700mg; 61.4%)

Step 4: Pd(PPh₃)₄ (177 mg, 0.154 mmol, 0.1 eq.) and Na₂CO₃ (244 mg,2.310 mmol, 1.5 eq.) were added to a stirred solution of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-cyclopropylaniline(400 mg, 1.540 mmol, 1.0 eq.) andN-(5-bromo-3-fluoropyridin-2-yl)-2-methylpyrimidine-5-carboxamide (478mg, 1.540 mmol, 1.0 eq.) in a mixture of dioxane (20 ml) and water (5ml) previously degassed with argon for 30 min. The reaction mixture washeated to 80° C. for 5 h after which time it was allowed to cool to RT.The reaction mixture was then filtered and the filtrate was concentratedunder reduced pressure. The crude residue was dissolved in ethyl acetatethen washed with water brine. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to obtain crude product whichwas purified by preparative HPLC to yieldN-{5-[3-(cyclopropylamino)phenyl]-3-fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide(68) (120 mg; 21.4%).

TABLE I Compound Chemical Name/ ID Structure ¹H-NMR (CDCl₃, 400 MHz) 1

N-(biphenyl-4-yl)pyrimidine-5- carboxamide/ δ 9.36 (s, 2H), 9.31 (s,1H), 9.50 (m, 2H), 8.15 (dd, 1H, J = 9.0, 2.2 Hz), 7.52 (d, 2H, J = 7.6Hz), 7.44 (t, 2H, J = 7.4 Hz), 7.39 (q, 1H, J = 7.4 Hz) 2

N-[5-(4-chlorophenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ ND 3

N-[5-(3-chlorophenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.35 (s,1H), 9.29 (s, 2H), 8.50 (d, 1H, J = 2.0 Hz), 8.41 (d, 1H, J = 8.8 Hz),7.95 (dd, 1H, J = 8.4, 2.4 Hz), 7.53 (m, 1H), 7.43-7.33 (m, 3H) 4

N-[5-(2-chlorophenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ ND 5

N-[5-(2-chlorophenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.35 (s,1H), 9.31 (s, 2H), 8.45 (d, 1H, J = 8.8 Hz), 8.27 (s, 1H), 7.91 (d, 1H,J = 8.4 Hz), 7.79 (d, 2H, J = 8.8 Hz), 7.58 (s, 1H) 6

N-(5-cyclopropylpyridin-2- yl)pyrimidine-5-carboxamide/ δ 9.37 (s, 1H),9.27 (s, 2H), 9.00 (bs, 1H), 8.25 (d, 1H, J = 8.8 Hz), 8.09 (d, 1H, J =2.0 Hz), 7.45 (dd, 1H, J = 8.6, 2.2 Hz), 1.90 (m, 1H, 4.4 Hz), 1.03 (m,2H), 0.71 (m, 2H) 7

N-[5-(thiophen-3-yl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.40 (s,1H), 9.34 (s, 2H), 8.54 (d, 1H, J = 1.6 Hz), 8.48 (d, 1H, J = 8.8 Hz),8.07 (dd, 1H, J = 8.8, 2.4 Hz), 7.52 (m, 1H), 7.47 (dd, 1H, J = 5.0, 3.0Hz), 7.37 (dd, 1H, J = 5.0, 1.4 Hz) 8

2-methyl-N-(5-phenylpyridin-2- yl)pyrimidine-5-carboxamide/ δ 9.19 (s,2H), 8.96 (bs, 1H), 8.53 (d, 1H, J = 2.0 Hz), 8.45 (d, 1H, J = 8.8 Hz),8.03 (dd, 1H, J = 8.4, 2.4 Hz), 7.57 (m, 2H), 7.48 (t, 2H, J = 7.6 Hz),7.40 (tt, 1H, J = 7.4, 2.4 Hz), 2.83 (s, 3H) 9

2-amino-N-(5-phenylpyridin-2- yl)pyrimidine-5-carboxamide δ 8.95 (bs,1H), 8.84 (bs, 1H), 8.45 (d, 1H, J = 2.0 Hz), 8.41 (d, 1H, J = 8.8 Hz),8.01 (dd, 1H, J = 8.8, 2.4 Hz), 7.51 (d, 2H, J = 7.2 Hz), 7.43 (t, 2H, J= 7.4 Hz), 7.35 (m, 1H), 3.32 (m, 1H), 3.02 (m, 3H) 10

N-(5-phenylpyridin-2-yl)pyridine-3- carboxamide/ δ 9.19 (d, 1H, J = 2.0Hz), 8.95 (bs, 1H), 8.80 (dd, 1H, J = 4.8, 1.60 Hz), 8.51 (d, 1H, J =2.0 Hz), 8.46 (d, 1H, J = 8.0 Hz), 8.27 (dt, 1H, J = 8.0, 2.0 Hz), 8.01(dd, 1H, J = 8.6, 2.2 Hz), 7.56 (m, 2H), 7.46 (m, 3H), 7.39 (m, 1H) 11

N-[5-(thiophen-2-yl)pyridin-2- yl]pyridine-3-carboxamide/ δ 9.19 (d, 1H,J = 0.8 Hz), 9.02 (bs, 1H), 8.81 (dd, 1H, J = 4.8, 0.8 Hz), 8.80 (dd,1H, J = 4.8, 1.60 Hz), 8.54 (d, 1H, J = 2.0 Hz), 8.45 (d, 1H, J = 8.8Hz), 8.29 (dt, 1H, J = 8.4, 2.0 Hz), 8.01 (dd, 1H, J = 8.8, 2.4 Hz),7.47 (dd, 1H, J = 8.0, 4.8 Hz), 7.34 (m, 2H), 7.11 (dd, 1H, J = 5.0, 3.8Hz) 12

N-(5-phenylpyrimidin-2- yl)pyrimidine-5-carboxamide/ δ 9.29 (s, 1H),9.24 (s, 2H), 8.82 (s, 2H), 7.51-7.39 (m, 5H) 13

N-(3,4′-bipyridin-6-yl)pyrimidine-5- carboxamide/ ND 14

N-(3,3′-bipyridin-6-yl)pyrimidine-5- carboxamide/ ND 15

N-(3,2′-bipyridin-6-yl)pyrimidine-5- carboxamide/ ND 16

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]pyrimidine-5-carboxamide/ δ 9.40(s, 1H), 9.32 (s, 2H), 9.15 (bs, 1H), 8.52 (d, 1H, J = 2.0 Hz), 7.46 (d,1H, J = 8.8 Hz), 8.04 (dd, 1H, J = 8.8, 2.4 Hz), 7.38-7.32 (m, 2H), 7.27(s, 1H), 7.09 (dt, 1H, J = 7.2, 1.4 Hz), 1.97 (qui, 1H, 4.2 Hz), 1.01(m, 2H), 0.74 (m, 2H) 17

N-{5-[3- (methylcarbamoyl)phenyl]pyridin- 2-yl}pyrimidine-5-carboxamide/δ 9.29 (s, 1H), 9.26 (s, 2H), 9.53 (d, 1H, J = 2.0 Hz), 8.35 (d, 1H, J =8.8 Hz), 7.99 (m, 2H), 7.71 (d, 1H, J = 7.2 Hz), 7.64 (d, 1H, J = 7.6Hz), 7.47 (t, 1H, J = 7.8 Hz), 2.94 (s, 3H) 18

N-[5-(3-methoxyphenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.35 (s,1H), 9.28 (s, 2H), 9.50 (d, 1H, J = 1.6 Hz), 8.37 (d, 1H, J = 8.8 Hz),7.96 (dd, 1H, J = 8.8, 2.4 Hz), 7.35 (t, 1H, J = 8.0 Hz), 7.12 (d, 1H, J= 7.6 Hz), 7.05 (t, 1H, J = 2.2 Hz), 6.90 (dd, 1H, J = 8.0, 1.6 Hz),3.93 (s, 3H) 19

N-[5-(furan-3-yl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.34 (s, 1H),9.31 (s, 2H), 8.98 (bs, 1H), 8.44 (d, 1H, J = 1.6 Hz), 8.40 (d, 1H, J =8.8 Hz), 7.92 (dd, 1H, J = 8.8, 2.4 Hz), 7.77 (s, 1H), 7.50 (s, 1H),6.68 (s, 1H) 20

N-[5-(furan-2-yl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.32 (s, 1H),9.28 (s, 2H), 8.59 (d, 1H, = 2.4 Hz), 8.36 (d, 1H, J = 8.8 Hz), 8.01(dd, 1H, J = 8.8, 2.8 Hz), 7.47 (d, 1H, J = 1.6 Hz), 6.68 (d, 1H, J =3.2 Hz), 6.47 (dd, 1H, J = 3.2, 1.6 Hz) 21

N-[5-(5-chloro-2- methoxyphenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ND 22

N-[5-(3-chloro-4- methoxyphenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ND 23

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]-2-methylpyrimidine-5-carboxamide/ δ 9.21 (s, 2H), 9.12 (bs, 1H), 8.50 (d, 1H, J = 2.0 Hz),8.46 (d, 1H, J = 8.4 Hz), 8.03 (dd, 1H, J = 8.6, 2.2 Hz), 7.38-7.32 (m,2H), 7.27 (m, 1H), 7.08 (m, 1H), 2.83 (s, 3H), 1.96 (qui, 1H, J = 4.2Hz), 1.02 (m, 2H), 0.75 (m, 2H) 24

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]pyridine-3-carboxamide/ δ 9.14(s, 1H), 8.72 (m, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.35 (d, 1H, J = 8.4Hz), 8.30 (dt, 1H, J = 6.4, 2.0 Hz), 7.96 (dd, 1H, J = 8.8, 2.0 Hz),7.27 (m, 1H), 7.48 (dd, 1H, J = 8.0, 4.8 Hz), 7.30 (m, 1H), 7.02 (m,1H), 1.92 (qui, 1H, J = 4.2 Hz), 0.97 (m, 2H), 0.71 (m, 2H) 25

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]-6-methylpyridine-3-carboxamide/ δ 9.06 (d, 1H, J = 2.0 Hz), 8.86 (bs, 1H), 8.49 (d, 1H, J =2.0 Hz), 8.44 (d, 1H, J = 8.8 Hz), 8.16 (dd, 1H, J = 8.2, 2.2 Hz), 7.98(dd, 1H, J = 8.8, 2.4 Hz), 7.37-7.27 (m, 4H), 7.07 (dt, 1H, J = 6.8, 2.2Hz), 2.64 (s, 1H), 1.96 (qui, 1H, J = 4.2 Hz), 1.01 (m, 2H), 0.75 (m,2H) 26

N-{5-[3- (cyclopropyloxy)phenyl]pyridin-2- yl}pyrimidine-5-carboxamide/δ 9.40 (s, 1H), 9.34 (s, 2H), 8.52 (d, 1H, J = 2.0 Hz), 8.50 (d, 1H, J =8.8 Hz), 8.07 (dd, 1H, J = 8.8, 2.4 Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.21(m, 1H), 7.16 (m, 1H), 7.12 (dd, 1H, J = 8.2, 1.8 Hz), 3.79 (qui, 1H, J= 2.8 Hz), 0.81 (m, 4H) 27

N-{5-[3- (cyclopropyloxy)phenyl]pyridin-2- yl}-2-methylpyrimidine-5-carboxamide/ δ 9.16 (s, 2H), 8.48 (d, 1H, J = 2.4 Hz), 8.31 (d, 1H, J =8.8 Hz), 7.97 (dd, 1H, J = 8.8, 2.0 Hz), 7.34 (t, 1H, J = 7.8 Hz), 7.17(m, 1H), 7.12 (m, 1H), 7.05 (dd, 1H, J = 8.2, 2.6 Hz), 3.79 (qui, 1H, J= 2.8 Hz), 2.78 (s, 3H), 0.76 (m, 4H) 28

N-{5-[3- (cyclopropyloxy)phenyl]pyridin-2- yl}pyridine-3-carboxamide/ δ9.11 (s, 1H), 8.70 (m, 1H), 8.47 (d, 1H, J = 1.2 Hz), 8.35 (m, 1H), 8.27(d, 1H, J = 8.8 Hz), 8.00 (dd, 1H, J = 8.6, 2.2 Hz), 7.52 (dd, 1H, J =7.8, 5.4 Hz), 7.32 (t, 1H, J = 8.0 Hz), 7.16 (m, 1H), 7.11 (m, 1H), 7.04(m, 1H), 3.73 (qui, 1H, J = 2.8 Hz), 0.74 (m, 4H) 29

N-{5-[3- (cyclopropyloxy)phenyl]pyridin-2- yl}-6-methylpyridine-3-carboxamide/ δ 9.07 (d, 1H, J = 2.0 Hz), 8.93 (bs, 1H), 8.51 (d, 1H, J =2.4 Hz), 8.46 (d, 1H, J = 8.4 Hz), 8.18 (dd, 1H, J = 8.2, 2.2 Hz), 8.00(dd, 1H, J = 8.8, 2.8 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.31 (d, 1H, J =8.0 Hz), 7.21 (t, 1H, J = 1.8 Hz), 7.16 (d, 1H, J = 7.6 Hz), 7.09 (m,1H), 3.79 (qui, 1H, J = 4.5 Hz), 2.65 (s, 3H), 0.81 (m, 4H) 30

N-{5-[3- (cyclopropylamino)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide/ δ 9.32 (s, 1H), 9.29 (s, 2H), 8.49 (m,1H), 8.37 (d, 1H, J = 8.8 Hz), 7.97 (dd, 1H, J = 8.4, 2.0 Hz), 7.24 (m,1H), 6.92 (s, 1H), 6.88 (d, 1H, J = 7.2 Hz), 6.79 (m, 1H), 2.42 (qui,1H, J = 3.2 Hz), 0.72 (m, 2H), 0.50 (m, 2H) 31

N-{5-[3- (cyclopropylamino)phenyl]pyridin- 2-yl}-2-methylpyrimidine-5-carboxamide/ δ 9.18 (s, 2H), 8.47 (m, 1H), 8.35 (d, 1H, J = 8.4 Hz),7.97 (dd, 1H, J = 8.8, 2.4 Hz), 7.23 (t, 1H, J = 7.6 Hz), 6.91 (m, 1H),6.87 (d, 1H, J = 7.2 Hz), 6.78 (m, 1H), 2.79 (s, 3H), 2.41 (qui, 1H, J =3.4 Hz), 0.71 (m, 2H), 0.50 (m, 2H) 32

N-{5-[3- (cyclopropylamino)phenyl]pyridin- 2-yl}pyridine-3-carboxamide/δ 9.17 (s, 1H), 8.80 (d, 1H, J = 4.4 Hz), 8.77 (m, 1H), 8.52 (d, 1H, J =2.0 Hz), 8.42 (d, 1H, J = 8.4 Hz), 8.26 (m, 1H), 7.98 (dd, 1H, J = 8.6,2.2 Hz), 7.47 (dd, 1H, J = 8.2, 4.6 Hz), 7.27 (t, 1H, J = 7.8 Hz), 6.93(m, 2H), 6.81 (m, 1H), 2.47 (qui, 1H, J = 3.2 Hz), 0.75 (m, 2H), 0.54(m, 2H) 33

N-{5-[3- (cyclopropylamino)phenyl]pyridin- 2-yl}-6-methylpyridine-3-carboxamide/ δ 9.06 (s, 1H), 8.84 (m, 1H), 8.47 (m, 1H), 8.41 (d, 1H, J= 8.8 Hz), 8.14 (d, 1H, J = 7.2 Hz), 7.95 (m, 1H), 7.28 (t, 2H, J = 6.8Hz), 6.92 (m, 1H), 6.79 (m, 1H), 2.63 (s, 3H), 2.47 (m, 1H), 0.76 (m,2H), 0.54 (m, 2H) 34

N-{5-[3-(4-methylpiperazin-1- yl)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide/ δ 9.39 (s, 1H), 9.27 (s, 2H), 8.68 (bs, 1H), 8.51 (d, 1H,J = 2.0 Hz), 8.38 (d, 1H, J = 8.4 Hz), 7.97 (dd, 1H, J = 8.6, 2.2 Hz),7.36 (t, 1H, J = 8.2 Hz), 7.07 (m, 1H), 7.04 (d, 1H, J = 7.6 Hz), 6.96(dd, 1H, J = 8.0, 2.0 Hz), 3.31 (m, 4H), 2.64 (m, 4H), 2.39 (s, 3H) 35

N-{5-[3-(4-methylpiperazin-1- yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 9.15 (s, 2H), 8.45 (d, 1H, J = 1.6Hz), 8.32 (d, 1H, J = 8.8 Hz), 7.91 (dd, 1H, J = 8.0, 2.2 Hz), 7.33 (t,1H, J = 8.0 Hz), 7.11 (d, 1H, J = 7.2 Hz), 7.04 (m, 1H), 6.91 (m, 1H),3.20 (m, 4H), 3.18 (m, 4H), 2.84 (s, 3H), 2.76 (s, 3H) 36

N-{5-[3-(4-methylpiperazin-1- yl)phenyl]pyridin-2-yl}pyridine-3-carboxamide/ δ 9.17 (d, 1H, J = 1.2 Hz), 8.80 (dd, 1H, J = 4.4, 1.2 Hz),8.64 (bs, 1H), 8.51 (d, 1H, J = 1.2 Hz), 8.41 (d, 1H, J = 8.8 Hz), 8.24(m, 1H), 7.95 (dd, 1H, J = 8.6, 2.2 Hz), 7.46 (dd, 1H, J = 8.0, 5.2 Hz),7.37 (t, 1H, J = 8.0 Hz), 7.09 (m, 2H), 6.95 (dd, 1H, J = 8.8, 1.6 Hz),3.45 (m, 4H), 2.91 (m, 4H), 2.58 (s, 3H) 37

N-{5-[3-(4-methylpiperazin-1- yl)phenyl]pyridin-2-yl}-6-methylpyridine-3-carboxamide/ δ 9.04 (s, 1H), 8.62 (s, 1H), 8.49 (d, 1H,J = 1.6 Hz), 8.40 (d, 1H, J = 8.8 Hz), 8.12 (dd, 1H, J = 8.2, 2.2 Hz),7.95 (dd, 1H, J = 8.8, 2.4 Hz), 7.35 (t, 1H, J = 7.8 Hz), 7.29 (d, 1H, J= 8.0 Hz), 7.07 (m, 1H), 7.04 (d, 1H, J = 7.6 Hz), 6.95 (m, 1H), 3.31(m, 4H), 2.64 (m, 7H), 2.39 (s, 3H) 38

N-{-5-[3-(2-(4-methylpiperazin-1- yl)ethoxy)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 9.16 (s, 2H), 8.65 (bs, 1H), 8.51 (d,1H, J = 2.0 Hz), 8.38 (d, 1H, J = 8.4 Hz), 7.96 (dd, 1H, J = 8.6, 2.2Hz), 7.36 (t, 1H, J = 8.0 Hz), 7.14 (d, 1H, J = 7.6 Hz), 7.09 (m, 1H),6.92 (dd, 1H, J = 8.0, 2.0 Hz), 4.16 (t, 2H, J = 5.8 Hz), 2.84 (t, 2H, J= 5.8 Hz), 2.83 (s, 3H), 2.65 (m, 4H), 2.50 (n, 4H), 2.30 (s, 3H) 39

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]-4-fluoropyridine-3-carbox-amide/ δ 9.07 (d, 1H, J = 12.0 Hz), 8.68 (d, 1H, J = 2.0 Hz), 8.64 (d,1H, J = 4.8 Hz), 8.54 (d, 1H, J = 1.6 Hz), 8.40 (d, 1H, J = 8.4 Hz),8.00 (t, 1H, J = 5.6 Hz), 7.96 (dd, 1H, J = 8.4, 2.0 Hz), 7.34 (m, 2H),7.27 (m, 1H), 7.07 (m, 1H), 1.96 (qui, 1H, J = 4.5 Hz), 1.01 (m, 2H),0.74 (m, 2H) 40

N-[5-(biphenyl-3-yl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 9.32 (s,1H), 9.30 (s, 2H), 8.57 (d, 1H, J = 1.6 Hz), 8.42 (d, 1H, J = 8.4 Hz),8.05 (dd, 1H, J = 8.6, 2.2 Hz), 7.73 (m, 1H), 7.59 (m, 3H), 7.51 (d, 2H,J = 5.2 Hz), 7.43 (t, 2H, J = 7.4 Hz), 7.34 (t, 2H, J = 7.4 Hz) 41

N-{5-[3-(oxetan-3- yl)phenyl]pyridin-2-yl}pyrimidine- 5-carboxamide/ δ11.2 (br s), 9.36 (s, 1H), 9.31 (s, 1H), 8.78 (d, 1H, J = 1.6 Hz), 8.25(m, 2H), 7.75 (bs, 1H), 7.65 (m, 1H), 7.49 (m, 2H), 4.9 (q, 2H, J = 6.8Hz), 4.72 (q, 2H, J = 6.8 Hz), 4.35 (qui, 1H, J = 8 Hz) 42

2-methyl-N-{5-[3-(oxetan-3- yl)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide/ ND 43

N-{5-[3-(oxetan-3- yl)phenyl]pyridin-2-yl}pyridine-3- carboxamide/ ND 44

6-methyl-N-{5-[3-(oxetan-3- yl)phenyl]pyridin-2-yl}pyridine-3-carboxamide/ ND 45

N-[5-(3-cyclobutylphenyl)pyridin- 2-yl]pyrimidine-5-carboxamide/ δ 9.36(s, 1H), 9.30 (s, 1H), 8.72 (bd, 1H, J = 2.0 Hz), 8.23 (m, 2H), 7.55 (m,2H), 7.46 (t, J = 8 Hz), 7.30 (d, J = 7.6 Hz), 3.61 (qui, 1H, J = 8.8Hz), 2.32 (m, 2H), 2.18 (m, 2H), 2.03 (m, 1H), 1.85 (m, 1H) 46

N-[5-(3-tert-butylphenyl)pyridin-2- yl]pyrimidine-5-carboxamide/ δ 11.4(bs, 1H) 9.36 (s, 1H), 9.31 (s, 1H), 8.72 (bd, 1H, J = 2.0 Hz), 8.28 (m,1H), 8.20 (m, 1H), 7.71 (bs, 1H), 7.53 (m, 1H), 7.44 (m, 2H), 1.37 (s,9H) 47

N-{5-[3-chloro-5-(4- methylpiperazin-1- yl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ ND 48

N-{5-[3-chloro-5-(4- methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ ND 49

N-{5-[3-cyclopropylsulfonyl-5-(4- methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ δ 11.39 (s,1H), 9.22 (s, 1H), 8.81 (s, 1H), 8.29 (m, 2H), 7.54 (d, 2H, J = 9.6 Hz),7.33 (s, 1H), 3.32 (m, 4H), 3.00 (m, 1H), 2.71 (s, 3H), 2.50 (bs, 4H),2.24 (s, 3H), 1.17 (m, 2H), 1.04 (m, 2H) 50

N-{5-[3-cyclopropylsulfonyl-5-(4- methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ δ 11.15 (s, 1H),9.22 (s, 2H), 8.12 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.34(s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 3.33 (m, 4H), 2.92 (m, 1H), 2.73(s, 3H), 2.55 (m, 4H), 2.45 (s, 3H), 2.28 (s, 3H), 1.16 (m, 2H), 1.10(m, 2H) 51

N-{5-[3-cycopropylamino-5-(4- methylpiperazin-1-yl)phenyl]pyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ δ 9.20 (s,2H), 8.62 (d, 1H, J = 2.0 Hz), 8.22 (d, 1H, J = 8.8 Hz), 8.08 (dd, 1H, J= 8.4 Hz, J = 2.9 Hz), 6.49 (d, 2H, J = 6.0 Hz), 6.32 (s, 1H), 3.17 (m,4H), 2.72 (s, 3H), 2.47 (m, 4H), 2.39 (m, 1H), 2.23 (s, 3H) 1.24 (s,1H), 0.71 (m, 2H), 0.39 (m, 2H) 52

N-{5-[3-cyclopropylamino-5-(4- methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ δ 9.21 (s, 2H),8.04 (d, 1H, J = 8.4 Hz), 7.63 (d, 1H, J = 8.4 Hz), 6.27 (s, 1H), 6.16(s, 2H), 6.02 (s, 1H), 3.17 (bs, 1H), 3.10 (bs 4H), 2.71 (s, 3H), 2.44(bs, 7H), 2.21 (bs, 3H), 1.23 (s, 1H), 0.67 (m, 2H), 0.37 (m, 2H). 53

N-{5-[3-cyclopropyl-5-(4- methylpiperazin-1-yl)phenyl]-6-methylpyridin-2-yl}-2- methylpyrimidine-5-carboxamide/ 11.31 (s, 1H),9.22 (s, 2H), 8.70 (s, 1H), 8.43 (bs, 3H), 8.24 (d, 1H, J = 8.8 Hz),8.15 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.0 (s, 1H), 6.81 (s, 1H), 6.68(s, 1H) 3.21 (m, 4H), 2.71 (s, 3H), 2.48 (m, 4H), 2.23 (s, 3H) 1.93 (m,1H), 0.93 (m, 2H), 0.76 (m, 2H) 54

N-{5-[3-chloro-5-(piperazin-1- yl)phenyl]-3-Fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 9.22 (s, 2H), 8.70 (s, 1H), 8.27 (d,1H, J = 11.6 Hz), 7.24 (m, 2H), 6.99 (s, 1H), 3.23 (bs, 4H), 2.85 (bs,4H), 2.75 (s, 3H) 55

2-methyl-N-{5-[3-(pyrrolidin-3- ylamino)phenyl]pyridin-2-yl}pyrimidine-5-carboxamide/ δ 11.41 (s, 1H), 9.31 (bs, 1H), 9.24 (s,1H), 8.68 (d, 1H, J = 2.4 Hz), 8.27 (d, 1H, J = 8.8 Hz), 8.16 (dd, 1H, J= 8.8 Hz, J = 2.2 Hz), 7.26 (t, 1H, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0Hz), 6.94 (s, 1H), 6.69 (d, 1H, J = 8.0 Hz), 4.23 (m, 1H), 3.45 (m, 1H),3.34 (m, 1H), 3.30 (m, 1H), 3.08 (m, 1H), 2.72 (s, 3H), 2.25 (m, 1H),1.92 (m, 1H) 56

2-[(2-aminoethyl)amino]-N-[5-(3- cyclopropylphenyl)pyridin-2-yl]pyrimidine-5-carboxamide/ δ 8.68 (dd, 2H, J = 21.0 Hz, J = 2.0 Hz),8.22 (d, 1H, J = 8.8 Hz), 8.12 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 8.03(dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.47 (d, 1H, J = 7.6), 7.35 (m, 2H),7.09 (d, 1H, J = 7.2 Hz), 3.47 (m, 2H), 2.88 (m, 2H), 2.02 (m, 1H), 1.8(bs, 4H), 1.00 (m, 2H), 0.77 (m, 2H) 57

N-{5-[3- (cyclopropyloxy)phenyl]pyridin-2- yl}-2-methoxypyrimidine-5-carboxamide/ δ 9.15 (s, 1H), 8.71 (d, 1H, J = 1.6 Hz), 8.25 (d, 2H, J =8.4 Hz), 8.18 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.45 (t, 1H, J = 8.0Hz), 7.36 (m, 2H), 7.12 (dd, 1H, J = 8.4 Hz, J = 2.0 Hz), 4.02 (s, 3H),3.95 (m, 1H), 0.83 (m, 2H), 0.69 (m, 2H) 58

2-[(2-aminoethyl)amino]-N-[5-(3- cyclopropyloxyphenyl)pyridin-2-yl]pyrimidine-5-carboxamide/ δ 8.69 (dd, 2H, J = 19.6 Hz, J = 2.0 Hz),8.23 (d, 1H, J = 8.8 Hz), 8.13 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 8.03(dd, 1H, J = 8.8 Hz, J = 1.6 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.33 (m,2H), 7.10 (m, 1H), 6.57 (d, 1H, J = 8.8 Hz), 3.94 (m, 1H), 3.46 (m, 2H),2.86 (m, 2H), 0.83 (m, 2H), 0.69 (m, 2H) 59

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]-2-methoxypyrimidine-5-carboxamide/ δ 11.19, (bs, 1H), 9.17 (s, 2H), 8.72 (d, 1H, J = 2.4 Hz),8.26 (d, 1H, J = 8.8 Hz), 8.17 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 7.49(d, 1H, J = 8.0 Hz), 7.43 (s, 1H), 7.36 (t, 1H, J = 7.2 Hz), 7.1 (d, 1H,J = 7.6 Hz), 4.0 (s, 3H), 2.0 (m, 1H), 0.97 (m, 1H), 0.79 (m, 1H) 60

N-[5-(3-cyclopropylphenyl)pyridin- 2-yl]-2-hydroxypyrimidine-5-carboxamide/ δ 9.89 (s, 1H), 8.69 (m, 1H), 8.58 (m, 1H), 8.37 (bs, 1H),8.15 (m, 2H), 7.41 (m, 2H), 7.08 (m, 1H), 2.01 (m, 1H), 1.00 (m, 2H),0.77 (m, 2H) 61

2-methyl-N-[5-(thiophen-3- yl)pyridin-2-yl]pyrimidine-5- carboxamide/ δ9.20 (s, 2H), 8.81 (s, 1H), 8.22 (d, 2H, J = 1.6 Hz), 7.99 (m, 1H), 7.66(m, 2H), 2.73 (s, 3H) 62

2-methyl-N-[5-(5-methylthiophen- 3-yl)pyridin-2-yl]pyrimidine-5-carboxamide/ δ 11.21 (s, 1H), 9.20 (s, 2H), 8.75 (d, 1H, J = 1.6 Hz),8.22 (d, 1H, J = 8.8 Hz), 8.16 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.73(d, 1H, J = 1.2 Hz), 7.35 (s, 1H) 2.71 (s, 3H), 2.50 (s, 3H) 63

N-{5-[3- (cyclopropylsulfonyl)phenyl]pyridin-2-yl}-2-methylpyrimidine-5- carboxamide/ δ 11.42 (s, 1H), 9.23 (s, 2H),8.85 (d, 1H, J = 1.2 Hz), 8.32 (m, 2H), 8.30 (bs, 1H), 8.14 (d, 1H, J =8.0 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 2.96 (q 1H,J = 3.6 Hz), 2.74 (s, 3H), 1.21 (m, 2H), 1.11 (m, 2H) 64

N-{5-[3- (cyclopropylsulfonyl)phenyl]-6- methylpyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 11.33 (bs, 1H), 9.21 (s, 2H), 8.16 (d,1H, J = 8.1 Hz), 7.92 (m, 2H), 7.79 (m, 3H), 2.95 (m 1H), 2.71 (s, 3H),2.46 (s, 3H), 1.17 (m, 2H), 1.07 (m, 2H) 65

N-[5-(3-cyclopropyl-5- hydroxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide/ δ 11.30 (s, 1H), 9.45 (s, 1H), 9.21 (s,2H), 8.65 (d, 1H, J = 2.4 Hz) 8.25 (d, 1H, J = 2.4 Hz), 8.10 (dd, 1H, J= 8.4 Hz, J = 2.4 Hz), 6.86 (m, 2H), 6.49 (s, 1H), 2.73 (s 3H), 1.92 (m,1H), 0.97 (m, 2H), 0.72 (m, 2H) 66

N-{5-[3-(cyclopropyloxy)phenyl]-3- fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ δ 11.20 (s, 1H), 9.22 (s, 2H), 8.68(s, 1H), 8.21 (dd, 1H, J = 11.2 Hz, J = 2.2 Hz), 7.44 (m, 3H), 7.15 (d,1H, J = 8.4 Hz), 3.97 (q, 1H, J = 3.2 Hz), 2.75 (s, 3H), 0.85 (m, 2H),0.69 (m, 2H) 67

N-[5-(3-cyclopropylphenyl)-3- fluoropyridin-2-yl]-2- methylpyrimidine-5-carboxamide/ δ 11.18 (s, 1H), 9.22 (s, 2H), 8.67 (s, 1H), 8.21 (dd, 1H,J = 11.2 Hz, J = 2.2 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.49 (s, 1H), 7.39(t, 1H, J = 7.2 Hz), 7.16 (d, 1H, J = 8.0 Hz), 2.73 (s, 3H), 2.01 (q,1H, J = 2.4 Hz), 1.00 (m, 2H), 0.82 (m, 2H) 68

N-{5-[3- (cyclopropylamino)phenyl]-3- fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 11.16 (s, 1H), 9.22 (s, 2H), 8.56 (s,1H), 8.06 (dd, 1H, J = 11.2 Hz, J = 2.0 Hz), 7.23 (t, 1H, J = 8.0 Hz),7.03 (s, 1H), 6.97 (d, 1H, J = 7.2 Hz), 6.78 (dd, 1H, J = 7.6 Hz, J =1.2 Hz), 6.26 (s, 1H), 2.73 (s, 3H), 2.41 (m, 1H), 0.73 (m, 2H), 0.41(m, 2H) 69

N-[3-fluoro-5-(thiophen-3- yl)pyridin-2-yl]-2- methylpyrimidine-5-carboxamide/ δ 11.15 (s, 1H), 9.22 (s, 2H), 8.77 (s, 1H), 8.27 (dd, 1H,J = 11.2 Hz, J = 2.0 Hz), 8.18 (t, 1H, J = 2.0 Hz), 7.74 (d, 2H, J = 2.0Hz), 2.73 (s, 3H) 70

N-{5-[3- (cyclopropylsulfonyl)phenyl]-3- fluoropyridin-2-yl}-2-methylpyrimidine-5-carboxamide/ δ 11.28 (s, 1H), 9.23 (s, 2H), 8.79 (s,1H), 8.37 (dd, 1H, J = 11.6 Hz, J = 2.0 Hz), 8.29 (s, 1H), 8.19 (d, 1H,J = 7.6 Hz), 7.96 (d, 1H, J = 8.0 Hz), 7.81 (t, 1H, J = 8.0 Hz), 3.02(m, 1H), 2.74 (s, 3H), 1.20 (m, 2H), 1.08 (m, 2H)

TABLE II Observed Com- Monomer General Exact pound Synthesis CarboxylicCoupling Yield Mass ID Procedure acid A Procedure (%) (M + H) 1 NApyrimidine-5-car- 1 40 277.3 boxylic acid 2 NA pyrimidine-5-car- 1 17.2311.0 boxylic acid 3 NA pyrimidine-5-car- 1 50 311.1 boxylic acid 4 NApyrimidine-5-car- 1 13.9 311.2 boxylic acid 5 NA pyrimidine-5-car- 127.3 413.2 boxylic acid 6 NA pyrimidine-5-car- 1 42.7 241.2 boxylic acid7 NA pyrimidine-5-car- 1 13.2 283.2 boxylic acid 8 NA 2-methylpyrimi- 216 291.0 dine-5-car- boxylic acid 9 NA 2-methylpyrimi- 1 8.4 306.0dine-5-car- boxylic acid 10 NA pyrimidine-3-car- 1 58 276.0 boxylic acid11 NA pyrimidine-3-car- 1 18 281.9 boxylic acid 12 G pyrimidine-5-car- 150 277.9 boxylic acid 13 NA pyrimidine-5-car- 1 63 277.1 boxylic acid 14NA pyrimidine-5-car- 1 19 277.1 boxylic acid 15 NA pyrimidine-5-car- 118 277.1 boxylic acid 16 A pyrimidine-5-car- 2 9.7 317.0 boxylic acid 17NA pyrimidine-5-car- 2 15 334.0 boxylic acid 18 NA pyrimidine-5-car- 218 307.0 boxylic acid 19 NA pyrimidine-5-car- 1 16 266.9 boxylic acid 20NA pyrimidine-5-car- 1 28 267.0 boxylic acid 21 K pyrimidine-5-car- 18.4 340.9 boxylic acid 22 L pyrimidine-5-car- 1 58 340.9 boxylic acid 23A 2-methylpyrimi- 2 25.4 331.0 dine-5-car- boxylic acid 24 Apyrimidine-3-car- 2 26.6 316.0 boxylic acid 25 A 6-methylpyri- 2 28.8330.0 dine-3-car- boxylic acid 26 B pyrimidine-5-car- 2 31.5 333.0boxylic acid 27 B 2-methylpyrimi- 2 32.6 347.0 dine-5-car- boxylic acid28 B pyridine-3-car- 2 30.8 332.0 boxylic acid 29 B 6-methylpyri- 2 29.6346.0 dine-3-car- boxylic acid 30 C pyrimidine-5-car- 2 27.2 332.0boxylic acid 31 C 2-methylpyrimi- 2 13 346.0 dine-5-car- boxylic acid 32C pyridine-3-car- 2 13.6 331.0 boxylic acid 33 C 6-methylpyri- 2 23345.0 dine-3-car- boxylic acid 34 D pyrimidine-5-car- 3 17.9 375.0boxylic acid 35 D 2-methylpyrimi- 3 20.7 389.0 dine-5-car- boxylic acid36 D pyridine-3-car- 3 32.3 374.0 boxylic acid 37 D 6-methylpyri- 3 27.7388.0 dine-3-car- boxylic acid 38 E 2-methylpyrimi- 2 31 433.0dine-5-car- boxylic acid 39 A 4-fluoropyri- 2 25.3 334.0 dine-3-car-boxylic acid 40 F pyrimidine-5-car- 2 34.4 353.0 boxylic acid 41 Hpyrimidine-5-car- 4 27.2 333.0 boxylic acid 42 H 2-methylpyrimi- 4 26.1347.0 dine-5-car- boxylic acid 43 H pyridine-3-car- 4 17.1 332.0 boxylicacid 44 H 6-methylpyri- 4 21.9 346.0 dine-3-car- boxylic acid 45 Ipyrimidine-5-car- 2 20.4 331.0 boxylic acid 46 J pyrimidine-5-car- 220.4 333.0 boxylic acid 47 M 2-methylpyrimi- 5 27.2 423.36 dine-5-car-boxylic acid 48 N 2-methylpyrimi- 5 4.3 437.26 dine-5-car- boxylic acid49 O 2-methylpyrimi- 5 9.5 493.3 dine-5-car- boxylic acid 50 P2-methylpyrimi- 5 13 507.5 dine-5-car- boxylic acid 51 NA NA NA NA444.34 52 NA NA NA NA 458.34 53 NA NA NA NA 429.5 54 NA NA NA NA 425.0855 NA NA NA NA 375.5 56 NA NA NA NA 374.13 57 B 2-methoxypyrimi- 5 12.5363.08 dine-5-car- boxylic acid 58 NA NA NA NA 390.11 59 A2-methoxypyrimi- 5 4.8 347.14 dine-5-car- boxylic acid 60 NA NA NA NA331.05 61 Q 2-methylpyrimi- 2 38.9 297.2 dine-5-car- boxylic acid 62 R2-methylpyrimi- 2 14 311.2 dine-5-car- boxylic acid 63 S 2-methylpyrimi-5 34.7 395.24 dine-5-car- boxylic acid 64 T 2-methylpyrimi- 5 32 409.13dine-5-car- boxylic acid 65 NA NA NA NA 347.2 66 U 2-methylpyrimi- 526.5 365.21 dine-5-car- boxylic acid 67 V 2-methylpyrimi- 5 21.8 349.24dine-5-car- boxylic acid 68 NA NA NA NA 356.2 69 W 2-methylpyrimi- 513.1 315.2 dine-5-car- boxylic acid 70 X 2-methylpyrimi- 5 32.7 413.19dine-5-car- boxylic acid

Tubulin Polymerization Assay

The Tubulin Polymerization Assay uses porcine neuronal tubulin andmeasurements are based on fluorescence enhancement due to theincorporation of a fluorescent reporter into microtubules aspolymerization occurs. The assay generates a polymerization curverepresenting the three phases of microtubule formation (nucleation,growth and equilibrium). IC₅₀ values for tested compounds can begenerated from the observed polymerization curves.

Procedure: All compounds dilutions (in DMSO) were prepared prior to thefollowing steps. A Molecular Devices M2 plate reader was set to 37° C.Once the internal temperature of the plate reader reached 37° C. a 96well plate (Corning Costar, at. #3686) was placed in the fluorimeter andallowed to warm to 37° C. for 30 minutes. A total of 10 mg of porcinetubulin was resuspended in 8 mL of Polymerization Buffer [Buffer 1 (80mM PIPES pH 6.9, 2.0 mM MgCl2, 0.5 mM EGTA, 1.0 mM GTP and 10 μMfluorescent reporter) supplemented with 20% glycerol] to generate a 2.0mg/ml tubulin stock and this was kept on ice. The 50× compound stocks in100% DMSO were spotted 1 μl/well in duplicate into the wells of the96-well plate at 37° C. and allowed to re-warm for 5 minutes at 37° C.During this incubation the 2.0 mg/ml tubulin stock was placed in adisposable plastic trough and allowed to warm briefly at roomtemperature. To initiate the reaction, 50 μl/well of 2.0 mg/ml tubulinin Polymerization Buffer was added to each well using a multi-channelpipettor and the fluorescence measurements were started immediately.

Data analysis: The fluorescence data acquired for tested compounds wasanalyzed as follows. The maximal velocity (V_(max)) of tubulinpolymerization was determined using linear regression of the averagedfluorescence data at each time point using GraphPad Prism 5.0 software.The V_(max) determinations for each compound at each concentration werethen normalized to reactions that contained DMSO (2% finalconcentration) but no test compounds. This converted the data to %Activity, which refers to the percent of the V_(max) of an uninhibitedreaction. The concentration response curves were then plotted as the %Activity versus the Log 10 of the compound concentration in micromolarand fit by non-linear regression to a 4-parameter sigmoidaldose-response equation using GraphPad Prism 5.0 software to determinethe IC50 for each compound.

Results from selected compounds tested are shown in Table III andcorrespond to compounds identified in Tables I and II as well as twocomparative compounds, namely vinblastine and vincristine.

TABLE III Compound IC₅₀ (μM) 1 1.4 3 1.45 16 0.48 23 0.89 27 0.68 310.32 44 0.30 61 0.26 63 0.24 64 0.12 66 3.84 67 2.42 68 1.98 69 2.35 700.01 Vinblastine 0.2 Vincristine 0.68

Cell Viability Assay Protocol

Cells were trypsinized, counted, and re-seeded into a 384-well tissueculture plate at 1000 cells per well in 25 mL media. Cells wereincubated at 37° C. in an atmosphere of 5% CO₂ for 24 hours.Experimental compounds, initially dissolved in DMSO and diluted furtherin media were added to the wells and incubated for 72 hours. Cellviability was measured using the ATPlite 1step Luminescence DetectionAssay system (Perkin Elmer) as described in the Assay kit instructions.Results with selected compounds are shown in Table IV.

Cell Culture Lines and Media: (1) A2780 cells were cultured in RPMImedia with 10% FBS and 1% antibiotics. Cells were typically split every3-5 days at a 1:10 dilution; (2) PC3 cells were cultured in RPMI mediawith 10% FBS and 1% antibiotics. Cells were typically split every 3-5days at a 1:4 dilution; (3) MCF-7 cells were grown in K-12F media with10% FBS and 1% antibiotics. Cells were typically split every 3-5 days ata 1:10 dilution.

TABLE IV Cell Cell Cell Cell Cell Cell Viability Viability ViabilityViability Viability Viability % inhibition % inhibition % inhibition %inhibition % inhibition % inhibition Compound A2780 A2780 MCF-7 MCF-7PC3 PC3 ID (20 uM Cpd) (4 uM Cpd) (20 uM Cpd) (4 uM Cpd) (20 uM Cpd) (4uM Cpd) 1 93.6 84.2 68.4 46.1 72.2 59.1 2 65.2 19.5 ND ND 17.4 4.9 390.2 84.8 56.8 50.6 68.3 60.9 4 87.5 79.7 ND ND 44.2 36.0 5 17.0 13.6 NDND 15.3 2.3 6 76.4 75.5 ND ND 29.9 27.0 7 90.9 81.3 ND ND 41.8 44.1 890.8 89.8 74.5 68.7 71.7 71.6 9 90.64 92.49 75.49 70.94 76.68 70.68 1095.25 92.73 86.43 61.35 87.26 71.83 11 97.8 85.0 88.9 58.6 83.8 70.0 1291.3 82.7 69.8 53.7 69.2 59.7 13 47.2 9.3 0.2 4.5 17.5 19.2 14 71.4 51.230.3 19.1 43.3 23.9 15 73.4 68.8 25.6 34.5 48.2 40.8 16 92.1 90.4 78.470.2 77.7 73.7 17 91.7 84.5 75.5 56.3 81.7 62.8 18 91.5 88.5 75.4 58.876.5 66.2 19 91.8 83.2 69.6 56.4 75.2 62.2 20 91.1 84.0 61.2 56.3 69.459.9 21 62.4 70.4 ND ND 15.3 22.8 22 67.9 69 ND ND 11.5 20.7 23 80.371.5 ND ND 66.2 53.7 24 72.2 73.4 ND ND 67.5 53.1 25 81.1 70.6 ND ND63.4 50.3 26 79.9 76 ND ND 67.5 59.3 27 77.4 77.3 ND ND 69.6 58.3 2874.2 77 ND ND 65.6 58.9 29 83.1 74.4 ND ND 69.5 60.5 30 78.7 77.4 ND ND71.9 63.4 31 71.2 70.9 ND ND 43.7 51.8 32 77 71.9 ND ND 57.6 57.3 3374.8 69.5 ND ND 54.9 56.1 34 49.4 51.6 ND ND 30.3 19.8 35 75.9 54.6 NDND 58.8 39.6 36 55.5 51.3 ND ND 42.5 24.3 37 70.8 59.2 ND ND 61 35.4 3868.7 51.7 ND ND 61.2 39.9 39 58.7 55.6 ND ND 28.7 19.2 40 72 61 ND ND52.5 48.3 41 88.9 74.7 ND ND 80.9 74.5 42 85.2 85 ND ND 84.5 80.3 4386.7 82.6 ND ND 84.5 75.1 44 86.1 86.5 ND ND 84.6 81.8 45 86.4 87.6 NDND 83.3 80.8 46 71.8 71.1 ND ND 67.6 68.5 47 95.5 88.7 64.6 40.6 78.663.2 48 88.8 79.2 47.8 36.5 67.0 72.0 49 59.5 16.9 48.3 28.1 39.7 19.450 62.6 7.3 40.7 10.0 54.7 39.2 51 76.0 6.8 49.5 22.9 65.7 17.3 52 69.58.0 22.2 −1.6 52.5 35.0 53 74.8 15.1 39.6 11.3 67.1 12.3 54 64.6 −6.442.6 23.8 34.8 0.2 55 87.4 80.3 ND ND 82.2 81.1 56 97.6 88.0 ND ND 97.481.4 57 89.8 88.3 ND ND 89.0 85.1 58 91.1 86.6 ND ND 93.6 77.7 59 90.487.8 ND ND 88.5 82.6 60 83.7 77.1 ND ND 80.6 48.8 61 89.7 86.5 72.9 73.370.6 58.3 62 89.9 85.2 67.0 59.4 65.1 54.8 63 88.0 85.6 65.1 59.1 67.661.4 64 81.5 80.0 74.5 73.5 62.7 59.4 65 89.8 85.9 ND ND 82.2 80.5 6688.4 89.0 76.0 75.0 70.6 66.0 67 87.9 87.1 63.7 60.0 61.6 56.0 68 89.087.1 59.3 54.3 64.4 58.4 69 90.1 84.7 61.3 56.2 64.5 57.6 70 87.8 86.366.1 61.1 65.0 58.4

1. A compound or salt of formula II

wherein X¹ is CR⁷; X² is selected from N and CR¹⁰; each of R¹, R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are —H; R³ is selected from substituted orunsubstituted C₃₋₆ cycloalkyl, —OR^(A), —NR^(A)R^(B), —SR^(A),—S(O)R^(A), —S(O)₂R^(A), and substituted or unsubstituted 3- to10-membered heterocyclyl; R¹¹ is selected from —H, halogen, substitutedor unsubstituted C₁₋₈ alkyl, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B),—OR^(A), and —NR^(A)R^(B); each of R^(A) and R^(B), when present, isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″,—NR′″C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; R′, R″, andR′″ are each independently hydrogen, unsubstituted C₁₋₄ alkyl, andsubstituted or unsubstituted C₃₋₆ cycloalkyl or R′ and R″ together withthe atoms which they substitute form a substituted or unsubstituted 5-,6-, or 7-membered ring.
 2. The compound or salt of claim 1, wherein R³is selected from cyclopropyl, —OCH₃, —O-cyclopropyl, —NH-cyclopropyl,—S(O)₂-cyclopropyl, oxetan-3-yl, cyclobutyl, —S(O)₂-cyclopropyl,piperazin-1-yl, and pyrrolidin-3-yl-amino.
 3. The compound or salt ofclaim 1, wherein R³ is —S(O)₂-cyclopropyl.
 4. The compound or salt ofclaim 1, wherein R³ is —O-cyclopropyl.
 5. The compound or salt of claim1, wherein R³ is —NH-cyclopropyl.
 6. The compound or salt of claim 1,wherein R³ is oxetan-3-yl.
 7. The compound or salt of claim 1, whereinthe compound or salt of formula II is


8. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier or excipient.
 9. A pharmaceuticalcomposition comprising a compound of claim 7 and a pharmaceuticallyacceptable carrier or excipient.
 10. A method of treating aproliferative disorder in a patient in need thereof, comprisingadministering a compound of claim 1 to the patient.
 11. The method ofclaim 10, wherein the proliferative disorder is a gastric cancer. 12.The method of claim 10, wherein the proliferative disorder is selectedfrom Castleman disease, gestational trophoblastic disease, and Hodgkinsdisease.
 13. A method of treating a proliferative disorder in a patientin need thereof, comprising administering a compound or salt of formulaII

wherein X¹ is CR⁷; X² is selected from N and CR¹⁰; each of R¹, R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are —H; R³ is selected from substituted orunsubstituted C₃₋₆ cycloalkyl, —OR^(A), —NR^(A)R^(B), —SR^(A),—S(O)R^(A), —S(O)₂R^(A), and substituted or unsubstituted 3- to10-membered heterocyclyl; R¹¹ is selected from —H, halogen, substitutedor unsubstituted C₁₋₈ alkyl, —C(O)R^(A), —CO₂R^(A), —C(O)NR^(A)R^(B),—OR^(A), and —NR^(A)R^(B); each of R^(A) and R^(B), when present, isindependently selected from —H, halogen, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR′R″, —OC(O)NR′R″,—NR′″C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′″CO₂R′, —SR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; R′, R″, andR′″ are each independently hydrogen, unsubstituted C₁₋₄ alkyl, andsubstituted or unsubstituted C₃₋₆ cycloalkyl or R′ and R″ together withthe atoms which they substitute form a substituted or unsubstituted 5-,6-, or 7-membered ring.
 14. The method of claim 13, wherein theproliferative disorder is cancer and is selected from adrenal, anal,aplastic anemia, bile duct, bladder, bone, brain, breast, cervical,central nervous system, colon, endometrial, esophagial, ewing family,ocular, gallbladder, gastrointestinal carcinoid, gastrointestinalstromal, Kaposi sarcoma, kidney, laryngeal, leukemia, liver, lung,lymphomas, malignant mesothelioma, multiple myeloma, myelodysplasticsyndrome, nasal cavity and paranasal sinus, nasopharyngeal,neuroblastoma, oral cavity and oropharyngeal, osteosarcoma, ovarian,pancreatic, penile, pituitary, prostate, rectal, retinoblastoma,rhabdomyosarcoma, salivary, sarcoma, skin, small intestine, stomach,testicular, thymus, thyroid, uterine sarcoma, vaginal, and Wilms tumorcancers.
 15. The method of claim 14, wherein the proliferative disorderis a gastric cancer.
 16. The method of claim 14, wherein theproliferative disorder is selected from Castleman disease, gestationaltrophoblastic disease, and Hodgkins disease.
 17. The method of claim 14,wherein the proliferative disorder is Castleman disease.
 18. The methodof claim 14, wherein the proliferative disorder is gestationaltrophoblastic disease.
 19. The method of claim 14, wherein theproliferative disorder is Hodgkins disease.
 20. The method of claim 14,further comprising administering an anti-cancer agent selected from thegroup consisting of: Aminoglutethimide; Asparaginase; Bleomycin;Busulfan; Carboplatin; Carmustine (BCNU); Chlorambucil; Cisplatin(cisDDP); Cyclophosphamide; Cytarabine HCl; Dacarbazine; Dactinomycin;Daunorubicin HCl; Doxorubicin HCl; Estramustine phosphate sodium;Etoposide (VP-16); Floxuridine; Fluorouracil (5-FU); Flutamide;Hydroxyurea (hydroxycarbamide); Ifosfamide; Interferon α-2a, α-2b,Lueprolide acetate (LHRH-releasing factor analogue); Lomustine (CCNU);Mechlorethamine HCl (nitrogen mustard); Melphalan; Mercaptopurine;Mesna; Methotrexate (MTX); Mitomycin; Mitotane (o.p′-DDD); MitoxantroneHCl; Octreotide; Plicamycin; Procarbazine HCl; Streptozocin; Tamoxifencitrate; Thioguanine; Thiotepa; Vinblastine sulfate; Vincristinesulfate; Amsacrine (m-AMSA); Azacitidine; Hexamethylmelamine (HMM);Interleukin 2; Mitoguazone (methyl-GAG; methyl glyoxalbisguanylhydrazone; MGBG); Pentostatin; Semustine (methyICCNU);Teniposide (VM-26); paclitaxel and other taxanes; Vindesine sulfate; andany combination thereof.